CN118078219A

CN118078219A - Near infrared fluorescence capture system, device and application

Info

Publication number: CN118078219A
Application number: CN202410495605.6A
Authority: CN
Inventors: 赵静; 许莹; 颜媛媛
Original assignee: Xindou Biotechnology Suzhou Co ltd
Current assignee: Xindou Biotechnology Suzhou Co ltd
Priority date: 2024-04-24
Filing date: 2024-04-24
Publication date: 2024-05-28

Abstract

The invention discloses a near infrared fluorescence capturing system, a near infrared fluorescence capturing device and application, wherein the capturing system is provided with an imaging module, and the imaging module is used for providing a fluorescence imaging agent for a targeted lesion area; the signal acquisition display module comprises a near infrared vision capturing device with a near infrared lens and a display device, and fluorescent signals emitted by a fluorescent imaging agent are acquired through the near infrared lens and are displayed in a tracing mode on the display device; a light source module for providing infrared excitation light to at least a lesion area targeted with a fluorescent imaging agent. According to the scheme, the targeted near infrared fluorescent imaging agent which can be matched with the near infrared fluorescent lens is adopted, so that lesions in operation can be identified, and the positive incisal margin rate and the false positive rate are reduced.

Description

Near infrared fluorescence capture system, device and application

Technical Field

The invention relates to biomedical technology, in particular to a near infrared fluorescence capture system, a near infrared fluorescence capture device and application.

Background

With the widespread popularity of endoscopic surgery and the rapid development of surgical robots, there is an increasing demand for precise intraoperative positioning and identification of surgery. Compared with the conventional open surgery, the intraoperative fluorescence visualization technology is vigorously developed under the wide application of a fluorescence endoscope, ICG fluorescent contrast agent and fluorescence surgery navigation hardware. The intraoperative fluorescence imaging can provide real-time identification of blood vessels, tumors, lymph nodes, nerves and the like during the operation, provides a new tool for accurately positioning the target part in the operation and searching the optimal surgical path, reduces the intraoperative hemorrhage and iatrogenic nerve injury, ensures the safety in the operation, and maximally avoids the injury to large blood vessels and nerves so as to shorten the extrahospital rehabilitation time of patients. ICG is still the most widely used near infrared contrast agent clinically at present.

Although ICG shows great potential in surgery, ICG has many drawbacks: such as inability to target a tumor due to lack of tumor specificity; repeated radiography is needed for many applications due to rapid metabolism; sentinel lymph nodes are inaccurately positioned due to tissue spread migrating to the lower lymph nodes; adding chemical instability, optical instability, etc. These drawbacks of ICG limit its application scenario. Many studies are currently performed by engineering ICG to prolong its fluorescence signal, improve tumor targeting and increase quantum yield and fluorescence stability. In one project, the authors developed ICG-lecithin-PEG-loaded core-shell nanoparticles of size 39nm, 68nm or 116 nm by nano-precipitation, comparing the excretion time of free ICG with that of nanoparticles, in a study exploring the effect of nanoparticle size on biodistribution and tumor accumulation. Fluorescence imaging showed that the retention time of the nanoparticle in vivo was longer than that of free ICG, which rapidly expelled from the body and cleared. They also concluded that ICG-PLGA nanoparticles present size-dependent tumor accumulation: 68nm particles can easily pass through the vessel aperture and have a slower clearance rate than 39nm particles (DOI: 10.1016/j. Biological. 2014.04.019). Takahito Nakajima et al designed the coupling of humanized anti-Prostate Specific Membrane Antigen (PSMA) antibodies (J591) to ICG. They obtained an activatable NIR probe capable of detecting psma+ tumors with high contrast compared to PSMA-tumors up to 10 days after injection of low dose agents. Its ability to be activated only in PSMA+ cells results in a very high tumor to background ratio (doi: 10.1021/bc 2002715). Wu et al developed a nanoparticle in which ICG was encapsulated in the core of a polymeric micelle made by self-assembly of an amphiphilic PEG-polypeptide hybrid triblock copolymer of polyethylene glycol-b-poly (L-lysine) -b-poly (L-leucine) (PEG-PLL-PLLeu), PLLeu being a hydrophobic core and PEG being a hydrophilic shell. ICG is associated with a hydrophobic core by hydrophobic interactions and with a hydrophilic head by electrostatic attraction interactions. PEG-PLL-PLLeu-ICG micelles significantly improved quantum yield and fluorescence stability compared to free ICG (DOI: 10.1021/bm400839 b).

A potential value of tumor-specific optical guidance is its ability to influence surgical decisions. Given that tumor surgery is guided primarily by visual and tactile cues, additional tumor-specific visualization layers can help navigate tumor border resection, diagnosis of secondary tumors, and regional lymphadenopathy. Ideally, the addition of fluorescent guidance to the surgical workflow does not disrupt standard practice, but rather enhances the ability of the surgeon to plan tumor resection, evaluate the resection bed, and analyze the edges of the resected specimen. After hours to days of pre-operative administration of the fluorescent agent, the tumor tissue can be visualized throughout the procedure using a specialized NIR camera system.

Meanwhile, the near infrared fluorescent lens has higher use rate in departments such as urology surgery, gynecology, general surgery, chest surgery and the like, and has lower use rate in other departments. The reason is that the fluorescent imaging agent which can be matched with the near infrared fluorescent lens is fresh. ICG is currently the most clinically used NIR fluorescence imaging agent, while ICG is most widely used in liver tumor resection, but ICG has some application drawbacks in its most suitable symptoms. Ishizawa et al report that in highly differentiated hepatocellular carcinoma (HCC), tumor tissue normally expresses a transporter (e.g., NTCP, OATP 8) and ingests ICG through the portal vein, often exhibiting total fluorescence. The expression of the above proteins is reduced in most medium and poorly differentiated HCC, and ICG uptake function is impaired, resulting in partial or complete non-fluorescent imaging of the tumor (DOI: 10.1002/CNCR.24291). Liver cells of patients suffering from liver cirrhosis are extensively necrotized, the massive proliferation of collagen fibers leads to the destruction of liver lobule structures, the nodular regeneration of residual liver cells, and ICG is retained in regenerated nodules due to bile excretion disorder, so that the false positive rate of ICG fluorescence imaging technology for recognizing tumors is obviously increased in patients suffering from liver cirrhosis. Tanaka et al examined the pathology of the total hepatectomy specimen of 10 liver cirrhosis patients receiving liver transplantation under a fluorescence microscope, the median node number identifiable by fluorescence was 20, the median of malignant tumors was confirmed to be 2 by the final pathology examination result, the rest was most regeneration nodes, and the positive predictive value was only 5.4% (DOI: 10.1002/JHBP.17), showing lower recognition efficiency.

The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.

Disclosure of Invention

The invention aims to provide a near infrared fluorescence capturing system, a near infrared fluorescence capturing device and application, and a fluorescence imaging agent which is matched with a near infrared lens to be used for helping to identify lesions in operation and reducing positive cutting edge rate and false positive rate.

To achieve the above object, embodiments of the present invention provide a near infrared fluorescence capturing system having an imaging module for providing the fluorescence imaging agent for targeting a lesion region, the fluorescence imaging agent being

M is selected from alkali metals;

The signal acquisition display module comprises a near infrared visual capturing device with a near infrared lens and a display device, and fluorescent signals emitted by the fluorescent imaging agent are acquired through the near infrared lens and are displayed in a tracing mode on the display device; and the light source module is at least used for providing infrared excitation light irradiation for a lesion area, and the lesion area is targeted with a fluorescent imaging agent. Preferably, the alkali metal represented by M is selected from potassium, sodium, etc., for example, the fluorescent imaging agent may be

。

In one or more embodiments of the invention, the wavelength of the infrared excitation light is 776-805nm.

In one or more embodiments of the present invention, an imaging module provides a fluorescence imaging agent for targeting a lesion area with an imaging fluid, the imaging fluid comprising a fluorescence imaging agent and an amount of water for injection, wherein the concentration of the fluorescence imaging agent is in a unit volume of 2 mL: 0.55 to 13.24 mg/bottle.

At this time, auxiliary agents such as sodium chloride, anhydrous citric acid, sodium citrate, sodium hydroxide, hydrochloric acid and the like can be added into the imaging liquid in proper amounts.

Specifically, an imaging fluid may be measured in 2mL per total volume:

，

Wherein, the proper amount of the components is added by the person skilled in the art according to experience and the prior art, wherein, the hydrochloric acid and the sodium hydroxide are pH regulators, the respective use amounts of the pH regulators are determined according to the pH conditions, and if the pH of the solution is 6.0-6.5 after the raw and auxiliary materials are completely dissolved, the use of the hydrochloric acid and the sodium hydroxide is not needed. If not, conditioning with sodium hydroxide or hydrochloric acid is required.

In one or more embodiments of the invention, the imaging fluid is administered intravenously.

In one or more embodiments of the invention, the imaging fluid is administered at a dose of, in terms of fluorescent imaging agent mass per unit weight: 0.01-1.5mg/kg.

In one or more embodiments of the invention, the imaging fluid is prepared as a sterile filtered manufacturing process.

In one or more embodiments of the present invention, the preparation of the imaging fluid is:

1) Weighing: weighing auxiliary materials and a fluorescent imaging agent according to the prescription amount;

2) Preparing: dissolving the auxiliary materials with a proper amount of water for injection to obtain an auxiliary material solution, adding the auxiliary material solution after dissolving the fluorescent imaging agent with the water for injection, and stirring until the solution is clear and transparent;

3) And (3) filtering: the fluorescent imaging agent solution is subjected to prefiltering, degerming and filtering to obtain the imaging liquid.

In one or more embodiments of the present invention, the pH of the solution in step 2) is controlled to be 5.9 to 7.0. Preferably, the pH is 6.0 to 6.5.

In one or more embodiments of the invention, the preparation of the imaging fluid:

1) Weighing: weighing adjuvants (such as sodium chloride, anhydrous citric acid, sodium citrate, sodium hydroxide, hydrochloric acid, water for injection, etc.) and fluorescent imaging agent according to the prescription.

2) Preparing: dissolving the auxiliary materials with a proper amount of water for injection, adding the auxiliary material solution after dissolving the fluorescent imaging agent with the water for injection, and stirring until the solution is clear and transparent. And taking the solution to measure the pH value, and controlling the pH value to be 5.9-7.0.

3) And (3) filtering: the fluorescent imaging agent solution is prefiltered by a 0.45 mu m PVDF filter, and then filtered by a two-stage 0.2 mu m PVDF sterilizing filter, thus obtaining the imaging liquid.

In one or more embodiments of the invention, the device comprises a body mainly used for bearing the rest functional structures; the functional structure is at least selected from: a power source and a near infrared fluorescence capture system as previously described, the power source selectively configured to power the signal acquisition module and/or the light source module.

In one or more embodiments of the present invention, the use of a near infrared fluorescence capture system as described above or a device as described above in near infrared fluorescence imaging guided surgery, the method of use comprising the steps of:

preparing an imaging fluid based on basic information of a target lesion area, the basic information being selected from at least: lesion site, age, sex, vascular condition, blood information, blood supply condition of target area;

selecting a drug supply mode and supplying drugs, after the fluorescent imaging agent finishes targeted adsorption, providing infrared excitation light for a target lesion area, and simultaneously acquiring and displaying real-time image signals by a signal acquisition and display module: the high response area is discriminated and/or stripped based on the real-time image signal. Before administration, the imaging liquid vial is taken out and thawed at room temperature in dark place, and then dissolved by glucose or sodium chloride solution, and the imaging liquid vial is stored at room temperature before administration.

Compared with the prior art, the near infrared fluorescence capturing system, the near infrared fluorescence capturing device and the application of the embodiment of the application help identify the pathological changes in operation and reduce the positive cutting edge rate and the false positive rate by adopting the targeting near infrared fluorescence imaging agent DGPR (namely the fluorescence imaging agent in the application) which can be matched with the near infrared fluorescent lens for use. The fluorescent imaging agent molecule is composed of three parts, DUPA and S0456 are connected through amino acid, wherein the DUPA targets PSMA, and the S0456 is a dye in a near infrared I region. The fluorescent imaging agent and the near infrared fluorescent lens of the application show more excellent characteristics than the prior art after being combined.

Firstly, the fluorescent imaging agent and the near infrared fluorescent lens are combined to overcome the defect of insufficient targeting in the prior art. The near infrared fluorescent dye ICG used clinically at present is not a specific marker of tumor cells, lacks targeting, cannot accurately identify tumors, and has high false negative and false positive proportion in operation. The preferred fluorescence imaging agent specifically targets the Prostate Specific Membrane Antigen (PSMA) which is overexpressed by the prostate cancer, and can effectively reduce the problems of false negative and high false positive in the operation process after being used together with a near infrared lens, for example, the excision of false positive tissues can influence the functions of urine control, erection and the like, and the false negative can generate miscut and the like.

And secondly, the fluorescent imaging agent and the near infrared fluorescent lens are combined to overcome the defect of high clearing speed from the body in the prior art. According to the pharmacological characteristics of ICG, the ICG is combined with serum proteins after intravenous injection, is taken up by liver cells, is secreted to bile by the liver cells in a free form, does not participate in vivo chemical reaction, has no intestinal liver circulation, no lymphatic countercurrent, and does not excrete from other extrahepatic organs such as kidneys, and the half-life is 3-4min. Too short half-life of ICG results in multiple infusions during surgery, severely affecting the quality of the procedure and extending the procedure time. The fluorescence imaging agent can still detect fluorescence after 24 hours of intravenous injection, shows strong contrast with the background, and can develop tumor by combining with a near infrared fluorescent lens.

And the fluorescent imaging agent and the near infrared fluorescent lens are combined to overcome the defect of low fluorescence quantum yield in the prior art. ICG typically has a fluorescence quantum yield of between 0.01 and 0.1, because ICG readily reacts with oxygen generation to cause ineffective non-radiative transitions, resulting in lower fluorescence quantum yields. ICG requires the use of higher doses clinically to maintain effective fluorescence intensity due to its lower fluorescence quantum yield. At present, indocyanine green is mostly applied in small doses (the recommended dose of indocyanine green in the specification is 0.5 mg/kg) in the multidisciplinary field, and is generally injected intravenously by 0.5mg/kg in liver metabolism tests, and the total ICG usage in cardiac output and blood volume detection is not more than 2mg/kg. The recommended dosage of the fluorescent imaging agent is far more than that of the fluorescent imaging agent, and the fluorescent imaging agent can provide effective fluorescence intensity under the dosage of 0.03mg/kg by combining with a near infrared fluorescent lens.

And the fluorescent imaging agent and the near infrared fluorescent lens are combined to overcome the defect of few indications in the prior art. The most clinically used near infrared fluorescence imaging agent ICG is limited in application range, is mainly applied to hepatectomy, and has few applications in other cancers such as renal cancer and lung cancer. Prostate Specific Membrane Antigen (PSMA) is not only overexpressed in prostate cancer patients, but also in neovasculature of solid tumors developing in organs and tissues such as liver, lung, breast cancer, colon, kidney, brain, sarcoma, stomach and oral cavity, so the application range of the combination of fluorescence imaging agent and near infrared fluorescence lens of the invention is wide.

Finally, the fluorescent imaging agent and the near infrared fluorescent lens are combined to overcome the defect that the tiny focus and the hidden lesion can not be found in the prior art. Because ICG lacks targeting, the hidden lesions cannot be well identified, resulting in a higher postoperative recurrence rate in patients. The fluorescent imaging agent provided by the invention can be combined with a near infrared fluorescent lens to find micro focus and hidden lesions.

Drawings

FIG. 1a is a fluorescence image of a tumor-bearing mouse 1h after injection of 10 nmol/mouse DGPR1008 and OTL78 in accordance with one embodiment of the invention;

FIG. 1b is a fluorescence image of a tumor-bearing mouse injected with 10 nmol/mouse DGPR1008 and OTL78 for 2h in vivo imaging, in accordance with one embodiment of the present invention;

FIG. 1c is a fluorescence image of a tumor-bearing mouse 4h after injection of 10 nmol/mouse DGPR1008 and OTL78 in accordance with one embodiment of the invention;

FIG. 1d is a fluorescence image of 8h in vivo imaging after injection of 10 nmol/mouse DGPR1008 and OTL78 into a tumor-bearing mouse according to one embodiment of the invention;

FIG. 1e is a fluorescence image of a tumor-bearing mouse 24h after injection of 10 nmol/mouse DGPR1008 and OTL78 in accordance with one embodiment of the invention;

FIG. 1f is a fluorescence image of a tumor-bearing mouse 72h after injection of 10 nmol/mouse DGPR1008 and OTL78 in accordance with one embodiment of the invention;

FIG. 2 is an in vitro tissue distribution of a tumor-bearing mouse injected with 10 nmol/mouse DGPR1008 and OTL782h according to one embodiment of the invention;

FIG. 3 is a mass spectrum of a fluorescence imaging agent DGPR1008 in accordance with one embodiment of the present invention;

FIG. 4 is an enlarged view of portion a of a mass spectrum of a fluorescence imaging agent DGPR1008 in accordance with one embodiment of the present invention;

fig. 5 is an enlarged view of portion b of a mass spectrum of a fluorescence imaging agent DGPR1008 in accordance with one embodiment of the present invention.

Detailed Description

The following detailed description of specific embodiments of the invention is, but it should be understood that the invention is not limited to specific embodiments.

Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising", etc. will be understood to include the stated element or component without excluding other elements or components.

The abbreviations used in the schemes of the present application have the meanings shown in the following table, and the remaining undefined parts are known to those skilled in the art and have the meanings consistent with the expression of the scheme of the present application.

In the following specific examples, the compounds of the following formula are examples of fluorescence imaging agents (DGPR) which are intended to illustrate one or several possible applications of the present invention, and are not intended to be limiting in any way. It should be noted that the compound is a sodium salt, excreted through the kidney, can be rapidly metabolized in non-targeted tissues and retained in diseased tissues, so that a mode of intravenous administration can be adopted 24 hours in advance, after metabolism for one day, the non-targeted tissues except tumor parts have no drug accumulation, and the tissues are irradiated in vivo or in vitro to develop diseased tissues expressing PSMA in surgery, such as a near infrared fluorescent lens-assisted surgery for collecting fluorescent signals in surgery, and the like.

DGPR1008 of the above formula is a Near Infrared (NIR) fluorescence imaging agent targeting Prostate Specific Membrane Antigen (PSMA), the mass spectrum of which is shown in fig. 3-5. The compound is used for combining a high-affinity PSMA targeting ligand DUPA and a near infrared fluorescent dye S0456 through a Linker (Linker), combining the high-affinity PSMA targeting ligand DUPA and the near infrared fluorescent dye S0456 with PSMA positive tumors with high affinity and specificity, and can be applied to Fluorescence Guided Surgery (FGS) to perform targeted tracking on tumors so as to identify positive edges and unidentified disease sites before operation. DGPR1008 molecules can be excited by external light with the wavelength of 776-805 nm, and emit near infrared light with the wavelength of 790-835 nm, and the maximum emission wavelength is 835nm.

Near Infrared (NIR) fluorescence imaging in operation is helpful for a surgeon to make judgment, reduces the positive rate of surgical margin, and has become an effective solution for detecting tumor margin in operation. The navigation in the fluorescence imaging is based on the enrichment of fluorescein in specific tissues, and can accurately display the information of blood vessels, lymph nodes, tumor tissues and the like in the operation. Meanwhile, the specific molecular targets in the tumor tissues can be specifically visualized, so that the effect of high signal-to-noise ratio tumor imaging is achieved, and the surgery incisional edge positive rate is further reduced. The wavelength range of near infrared light is 650nm to 900nm, and the penetration depth of the near infrared light in tissues can reach 10mm, so that the near infrared light is superior to visible light in the aspect of imaging in operation. Since tissue shows only limited autofluorescence in the NIR spectrum, the contrast between fluorescence signals in tumor and healthy tissue can be maximized using NIR fluorescence imaging agents. In addition, near infrared light does not affect the surgical field, as near infrared light is not visible to the human eye. Currently available imaging systems combine white light illumination of the surgical field with NIR fluorescence images, while providing anatomical and fluorescence information to the surgeon.

The near infrared fluorescent lens is a precondition for realizing near infrared fluorescent imaging. Near infrared fluorescent lenses are a special type of camera for medical and diagnostic use, commonly used in endoscopy and surgery. The near infrared fluorescent lens is mainly composed of an optical system and an image sensor, and can be introduced into a human body through an endoscope, so that the condition of internal organs and tissues can be observed and recorded. The near infrared fluorescent lens generally adopts a miniaturized design and has the characteristics of high definition, high sensitivity, high resolution and the like. The optical system can amplify and focus the observed object, convert the observed object into an electronic signal, and transmit the image to a display through an image sensor, so that a doctor can clearly observe and diagnose. The near infrared fluorescent lens has a very wide application range and can be used for examination and operation of a plurality of systems such as gastrointestinal tract, respiratory tract, genitourinary system, cardiovascular system, nervous system and the like. The device has the advantages of minimally invasive, high precision, high safety, low trauma and the like, and has become one of the indispensable important tools in modern medical treatment and diagnosis.

Prostate Specific Membrane Antigen (PSMA) is a type II transmembrane glycoprotein consisting of 750 amino acids, which has a molecular weight of more than 100 kD after glycosylation, and is expressed in non-prostate tissues such as the duodenum, the kidney, the salivary gland, the neuroendocrine system, and the proximal tubular, except in the prostate, but the expression of PSMA in prostate cancer tissues can be raised 100 to 1000 fold as compared to normal tissues, and is also overexpressed in cancerous lymph nodes and bone metastases, and the proportion of PSMA expressed in prostate cancer tumors is very high, almost all stages of the disease. In one Immunohistochemical (IHC) analysis, PSMA expression was detected in 94% of prostate cancer samples. In addition, increased PSMA expression is associated with tumor classification, pathological stage, and biochemical recurrence. And the transmembrane conformational structure of PSMA enables internalization of the binding agent by the endosomal complex, which is highly advantageous for successful targeting of the ligand.

DGPR1008 the molecule consists of three parts, DUPA and S0456 are linked by amino acids, wherein the polypeptide ligand part is DUPA, which is a glutamic acid urea and is one of the small molecule ligands with highest PSMA affinity, S0456 is a dye in the near infrared i region, which can be excited by external light of wavelengths 776-805 nm, and emits near infrared light of wavelengths 790-835 nm. The near infrared fluorescent lens collects tissue images through an optical path (comprising a mirror, an optical adapter and the like), and separates white light and fluorescent images through a light splitting mode, and then processes, fuses and displays the white light and the fluorescent images respectively, so that a precise operation image is provided for doctors.

According to the technical scheme, a 22Rv1 (PSMA+human prostate cancer cell line) subcutaneous tumor-bearing mouse model is constructed on a Balb/c nunu (athymic) nude mouse, and when the tumor volume reaches 300-400mm ³, DGPR1008 of 10 nmol/mouse is injected into the body of the mouse, and whole-body imaging and in-vitro tissue imaging are carried out by using a small animal living body imager with a near infrared fluorescent lens so as to observe DGPR tumor targeting capacity and tissue distribution.

Example 1

1 In vivo Living imaging study

A22 Rv1 (PSMA+human prostate cancer cell line) prostate cancer subcutaneous tumor-bearing mouse model was constructed on Balb/c nunu (athymic) nude mice and administered when tumor volume reached 300-400mm ³. Mice bearing 22Rv1 (psma+human prostate cancer cell line) tumor transplants were intravenously injected with 10 nmol/mouse DGPR and OTL78 (saline solution, the same applies below) and then subjected to whole body imaging studies using a small animal in vivo imaging system, the imaging device containing near infrared fluorescent lenses. Imaging was performed at time points of 1h, 2h, 4h, 8h, 24h, 72h, respectively, with specific results shown in fig. 1 a-1 f and table 1 below. In DGPR1008 dosing groups, at 1h, mice were covered by fluorescence throughout their body and were not able to distinguish well between tumor and non-tumor sites; the tumor and the background part can be clearly distinguished at the time point of 2h, the same degree of distinguishing the background of the tumor at 4h and 8h is more and more obvious, the time is continued to 24h, and the tumor and the background can still be well distinguished; after 72 hours of administration, fluorescence was still detectable in mice, and was substantially enriched at the tumor site, with little fluorescence detected by other tissues. The result shows that DGPR and 1008 combined with the near infrared fluorescent lens can realize the distinction between tumor and background in the mouse body at the fastest speed of 2 hours, and the fluorescence in the tumor can be continued until 24 hours later.

As can be seen in combination with table 1 and fig. 1 a-1 f:

1) At each time point, the fluorescence value of DGPR and 1008 tumor parts is larger than that of the original grinding medicine OTL78;

2) DGPR1008 is slower in the elimination metabolism in mouse tumor than OTL78;

3) The compound of this example showed good Tumor Background Ratio (TBR) in 2-4 h.

2 In vitro tissue 2h imaging- -tissue distribution study

A22 Rv1 (PSMA+human prostate cancer cell line) prostate cancer subcutaneous tumor-bearing mouse model was constructed on Balb/c nunu (athymic) nude mice and administered when tumor volume reached 300-400mm ³. The mice bearing the 22Rv1 tumor engraftment tumor were intravenously injected with 10 nmol/mouse DGPR and OTL78, and after 2 hours the dissected tissue was subjected to in vitro tissue imaging study, the specific results are shown in fig. 2, and the fluorescence ratio of the tumor to the prostate tissue of the mice was calculated, see table 2 below:

3 tumor-bearing mice in each group were dissected 2h after dosing, tumor, heart, lung, liver, kidney, spleen, muscle, stomach, intestine, skin, pancreas and prostate were taken for in vitro tissue imaging, and the imaging device contained near infrared fluorescent lenses. As can be seen from fig. 2, the tumors and kidneys of 6 mice had very bright fluorescence, and DGPR and OTL78 were both concentrated mainly at the tumor and kidney sites, with less distribution in other tissues.

The data from table 2 and fig. 2 can be combined to conclude that: when the compound of the embodiment is used as an identification aid, the compound has obvious signal intensity ratio in tumor/normal prostate tissues, which can fully reflect the capability of the drug to distinguish normal prostate from diseased prostate. The DGPR of this example showed a stronger discrimination (about 5 times), a higher Tumor Background Ratio (TBR), which can make the tumor border clearer during surgery and more accurate margin, than OTL 78. DGPR1008 is expected to be clinically useful to achieve higher Tumor Background Ratios (TBR) at doses below 0.03mg/kg (the clinical dose of OTL 78).

In addition, as can be seen from the pharmacokinetic parameters of 2mg/kg plasma of the rat, the average clearance rate of OTL78 is 3.50mL/min/kg, and the average clearance rate of DGPR1008 in the embodiment is 5.23mL/min/kg, which means that DGPR is metabolized faster in the rat body, and the safety factor is correspondingly improved. In the acute toxicity test of rats, no toxic reaction is observed in the high, medium and low dose groups, and the DGPR1008 compound of the embodiment is proved to have good safety.

As shown in table 1,3 22Rv1 (psma+human prostate cancer cell line) tumor-bearing mice, animals numbered 94772, 94779, and 94780, were dosed when tumors grew to a volume of 300-400mm ³. Each mouse was intravenously injected with 10 nmol/mouse DGPR and tumor and prostate tissues were dissected 2h after administration, and the fluorescence intensities of tumor and prostate tissues were measured by photographing with a small animal biopsy imager containing near infrared fluorescent lenses. The tumor fluorescence intensity of 94772 mice is 1.09E+10, the fluorescence intensity of prostate tissue is 2.17E+08, and the ratio of the tumor site to the prostate tissue is 50.2; the tumor fluorescence intensity of 94779 mice was 8.18E+09, the fluorescence intensity of prostate tissue was 2.41E+08, and the ratio of the fluorescence intensity of tumor sites to that of prostate tissue was 33.9; the tumor fluorescence intensity of 94780 mice is 9.42E+09, the fluorescence intensity of prostate tissue is 5.96E+08, and the ratio of the tumor part to the prostate tissue is 15.8; the average fluorescence intensity of tumors of 3 mice was 9.50E+09, the average fluorescence intensity of prostate tissue was 3.51E+08, and the average fluorescence intensity ratio of tumor sites to prostate tissue was 33.3.

Conclusion: DGPR1008 and 1008 combined with a near infrared fluorescent lens can carry out fluorescence development on tumors and various organs in vitro, and when the time is 2 hours, DGPR and 1008 are mainly distributed in the tissue as follows: tumors and kidneys, primarily because ① DGPR1008,1008 target the PSMA receptor that is overexpressed in tumor tissue; ② The medicine is excreted via kidney. As shown in table 2, the average value of the fluorescence intensity ratio of subcutaneous tumor to normal prostate tissue is 33.3, the average value of otl78 is 6.61, which suggests that DGPR and 1008 in combination with near infrared fluorescence lens have a stronger ability to distinguish diseased prostate tissue from normal prostate tissue, and are expected to provide clear boundary lines in surgery.

The foregoing descriptions of specific exemplary embodiments of the present invention are presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application to thereby enable one skilled in the art to make and utilize the invention in various exemplary embodiments and with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims

1. A near infrared fluorescence capture system has an imaging module for providing a fluorescence imaging agent for targeting a lesion region, the fluorescence imaging agent being

M is selected from alkali metals;

The signal acquisition display module comprises a near infrared visual capturing device with a near infrared lens and a display device, and fluorescent signals emitted by the fluorescent imaging agent are acquired through the near infrared lens and are displayed in a tracing mode on the display device;

And the light source module is at least used for providing infrared excitation light irradiation for a lesion area, and the lesion area is targeted with the fluorescent imaging agent.

2. The near infrared fluorescence capture system of claim 1, wherein the wavelength of the infrared excitation light is 776-805nm.

3. The near infrared fluorescence capture system of claim 1, wherein the imaging module provides a fluorescence imaging agent for targeting a lesion area with an imaging fluid, the imaging fluid comprising at least a fluorescence imaging agent and an amount of water for injection, wherein the concentration of the fluorescence imaging agent is in a unit volume of 2 mL: 0.55 to 13.24 mg/bottle.

4. The near infrared fluorescence capture system of claim 3, wherein said imaging fluid is administered intravenously.

5. The near infrared fluorescence capture system of claim 4, wherein the imaging fluid is administered at a dose of, in terms of fluorescence imaging agent mass per unit weight: 0.01-1.5mg/kg.

6. The near infrared fluorescence capture system of claim 4, wherein the imaging fluid is prepared by:

7. The near infrared fluorescence capturing system according to claim 6, wherein the pH of the solution in step 2) is controlled to be 5.9-7.0.

8. The device comprises a machine body mainly used for bearing other functional structures; the functional structure is at least selected from: a power supply and near infrared fluorescence capture system according to any of claims 1-7, said power supply being selectively operable to power said signal acquisition module and/or light source module.

9. Use of a near infrared fluorescence capture system according to any of claims 1-7 or a device according to claim 8 in near infrared fluorescence imaging guided surgery, the method of application comprising the steps of:

Selecting a drug supply mode and supplying drugs, after the fluorescent imaging agent finishes targeted adsorption, providing infrared excitation light for a target lesion area, and simultaneously acquiring and displaying real-time image signals by a signal acquisition and display module: the high response area is discriminated and/or stripped based on the real-time image signal.

10. The use according to claim 9, wherein the imaging fluid is stored at-25 ℃ to-15 ℃ after preparation.