Therapeutic equipment for reducing positive incisal margin after radical prostate resection

Abstract

The invention discloses treatment equipment for reducing positive incisal margin after radical prostate resection, which comprises an injection device for injecting a PSMA probe into a body, a PET / CT (positron emission tomography / computed tomography) imaging device, a near-infrared fluorescence imaging device and a surgical robot, and is characterized in that the near-infrared fluorescence imaging device displays fluorescence levels of tumor tissues and normal tissues of the prostate of a patient injected with the probe; and carrying out fluorescence imaging on the prostate tumor tissue according to the fluorescence intensity of the probe in the urine. The treatment equipment disclosed by the invention is used for carrying out fluorescence imaging and accurate positioning on tumor tissues in an excision operation, the surgical robot is used for accurately excising the tumor tissues under fluorescence navigation, and the postoperative excision edge positive rate is obviously reduced; after the treatment equipment is adopted to carry out radical prostate resection, the biochemical recurrence risk of a patient is obviously reduced, and the prognosis is good; in addition, complications such as erectile dysfunction, urinary incontinence and urethrostenosis caused by injury of nerve and blood vessel bundles in an operation can be avoided, and the influence on the postoperative life quality of a patient is remarkably reduced.

Description

Technical Field

[0001] The invention relates to a treatment device for prostatectomy, in particular to a treatment device for reducing the positive cutting edge after radical prostatectomy, and belongs to the field of medical equipment. Background Art

[0002] Prostate cancer is one of the most common malignant tumors of the male urogenital system. Its global morbidity and mortality rates remain high, ranking second and fifth in the spectrum of male malignant tumors and mortality, respectively. In China, the morbidity and mortality of prostate cancer have also shown an increasing trend year by year, posing a serious threat to men's health. Radical prostatectomy (RP) is a classic method for treating localized and locally advanced prostate cancer. In recent years, with the high-definition magnified three-dimensional field of view and flexible robotic arms with more degrees of freedom, robot-assisted radical prostatectomy (RARP) is becoming the mainstream surgical treatment for prostate cancer. RARP can significantly improve surgical accuracy and has significant advantages in short-term urinary control, sexual function, short-term complications, etc., while achieving the same oncological outcomes as traditional open surgery.

[0003] The key to the success of RARP is to completely remove the tumor tissue while preserving the surrounding important functional structures to the greatest extent. In order to achieve these two goals at the same time, it is particularly important to accurately identify the tumor boundary during surgery. The rapid development of prostate cancer-specific imaging technology has greatly improved the accuracy of prostate cancer diagnosis and staging. However, surgeons still rely mainly on their own experience during surgery, combined with limited visual information such as color, texture and morphology, and tactile information such as hardness or surface smoothness, to distinguish prostate cancer tissue from non-cancerous tissue. This subjective judgment method has a high positive surgical margin (PSM) rate. The current positive surgical margin rate of RP is as high as 6-50%, and PSM will increase the risk of biochemical recurrence after surgery and affect the patient's prognosis.

[0004] In recent years, near-infrared fluorescence intraoperative navigation technology has opened up a new path for the precision treatment of prostate cancer. During RARP, Manny et al. injected the fluorescent imaging agent indocyanine green (ICG) into the patient's prostate, successfully marking the prostate tissue and sentinel lymphatic network, effectively distinguishing the prostate from the surrounding neurovascular bundles, vas deferens and other structures, and effectively distinguishing the lymph nodes from the adjacent nerves and blood vessels, significantly reducing the risk of accidental injury to surrounding blood vessels and nerves during surgery. However, ICG is non-tumor specific and cannot specifically distinguish between lymph nodes with tumor metastasis and normal lymph nodes, nor can it distinguish between tumor tissue and normal tissue of the prostate. Therefore, highly specific targets are needed for precise imaging to achieve more accurate intraoperative navigation.

[0005] Studies have found that prostate specific membrane antigen (PSMA) is specifically overexpressed on the surface of 90% of prostate cancer cells (100-1000 times), and its expression level is closely related to the invasion and malignancy of the tumor. This target is used for radionuclide imaging and radioligand therapy of prostate cancer, and is an ideal biomarker for precise positioning and imaging of prostate cancer lesions. Fluorescent probes targeting PSMA generally consist of three parts: PSMA targeting group, spacer group and fluorophore. Among them, the targeting group is usually a small molecule inhibitor targeting PSMA to ensure efficient affinity with PSMA protein. Fluorescent groups often use near-infrared fluorescent dyes, such as indocyanine green, IRDye800RS, IRDye800CW, Cy7, Cy5.5 and corresponding derivatives. Near-infrared dyes are combined with PSMA targeting groups to synthesize a series of fluorescent probes targeting PSMA, thereby realizing real-time fluorescence imaging of PSMA-positive lesions during surgery. Fluorescent probes targeting PSMA have high affinity with PSMA protein and can achieve specific fluorescence imaging in tumors.

[0006] Existing PSMA-targeted probes are divided into single-modality near-infrared fluorescent probes and radionuclide / fluorescence dual-modality molecular imaging probes. However, due to the limited penetration depth of single-modality near-infrared fluorescent probes, it is difficult to identify deeper tumor foci. For patients who plan to undergo intraoperative navigation with near-infrared fluorescent probes targeted to PSMA, they need to wait for a period of time after PSMA PET / CT until the radionuclide imaging probe is cleared before the fluorescent probe can be injected for surgical navigation, which affects the timing of treatment for patients. Dual-modality molecular imaging probes integrate infrared fluorescent dyes and radioactive isotopes into a single ligand to overcome the defects of single imaging technology and achieve the dual functions of preoperative whole-body functional imaging and intraoperative precise fluorescence navigation. In the diagnosis and treatment of prostate cancer, dual-modality probes can not only effectively evaluate tumor staging through preoperative PET / CT or PET / MRI imaging, but also accurately identify tumor boundaries during surgery with the help of fluorescence imaging technology, and reflect the lesion size, infiltration range and lymph node metastasis in real time and intuitively, providing an important basis for clinical decision-making.

[0007] At present, a number of fluorescent probes targeting PSMA have been developed, among which: 1) OTL78 and IS-002, probes derived from Glu-Urea inhibitors, have been clinically studied; and these two clinical trials have preliminarily verified that the PSMA-targeted fluorescent probes OTL78 and IS-002 are safe in the human body. With the help of this type of probe and near-infrared fluorescence imaging technology, the PSM rate can be reduced, the accuracy of lymph node dissection can be improved, and better treatment effects can be brought to patients; 2) The PSMA probe based on ODAP-Urea has a high tumor uptake, and its in vivo metabolism is comparable to that of existing PSMA probes, and it is highly safe for in vivo use, without drug-related adverse reactions; and the PSMA radionuclide / fluorescence dual-modality probe based on ODAP-Urea has low radioactive concentration in the bladder, which can not only locate and qualitatively metastatic lesions, but also has good performance in the precise positioning and staging of lesions inside the prostate of patients with early prostate cancer. It is a very potential PSMA-targeted positron molecular probe.

[0008] The PSMA probe used in the therapeutic device for reducing the positive resection margin after radical prostatectomy of the present invention is derived from the ODAP-Urea inhibitor, with DOTA as a radionuclide chelator and an indocyanine green derivative as a fluorophore. The metabolic kinetic properties of the probe are optimized by a carboxylic acid-modified linker. Based on the molecule P137 of the structural formula (1), four PSMA-targeted radionuclide fluorescence dual-modal molecular imaging probes P1-P4 based on the ODAP-Urea skeleton are designed and synthesized, as shown in formula (2).

[0009]

[0010] Wherein, in formula (2), n=1, 2, 3, 4.

[0011] The research group of this invention found that the dual-mode PSMA probe 68 The uptake of Ga-P1-P4 in the tumor area is significantly higher than that in other non-target areas, and it can be specifically concentrated in the tumor area in near-infrared I zone optical imaging. Therefore, the present invention uses the dual-modality PSMA probe for the treatment device of the present invention. After the dual-modality probe is injected, the tumor area and the surrounding tissue can be clearly distinguished according to its fluorescence imaging (brightening tumor tissue), and combined with the PET imaging display results, it is used for near-infrared I zone fluorescence navigation of radical prostatectomy. Summary of the invention

[0012] The purpose of the present invention is to provide a treatment device for reducing the positive surgical margin after radical prostatectomy, in order to address the technical problems that existing equipment or devices for radical prostatectomy have difficulties in distinguishing tumor tissue from non-tumor tissue during surgery and have a high positive surgical margin rate. During the treatment process, the treatment device of the present invention can realize preoperative PET imaging through a radionuclide fluorescence dual-modality probe targeting PSMA to clarify the location of the tumor lesion, and can use intraoperative near-infrared fluorescence imaging to outline the tumor tissue boundary in real time, accurately locate the tumor tissue and define the tumor tissue boundary, reduce the positive surgical margin rate of radical prostatectomy, and reduce the risk of postoperative tumor residual.

[0013] To achieve the purpose of the present invention, the present invention provides a therapeutic device for reducing the positive resection margin after radical prostatectomy, comprising:

[0014] An injection device for injecting a PSMA-targeted radionuclide / fluorescence dual-modality molecular probe, i.e., a PSMA probe, into a patient's body;

[0015] A PET / CT imaging device for showing the general location of a prostate tumor in a patient injected with a PSMA probe;

[0016] A near-infrared fluorescence imaging device for displaying the fluorescence levels of tumor tissue and normal tissue in the prostate of a patient injected with a PSMA probe;

[0017] A surgical robot for completely removing the prostate and tumor tissue of a patient according to the general location of the patient's prostate tumor displayed by a PET / CT imaging device and the location of the tissue positively displayed by an intraoperative near-infrared fluorescence imaging device;

[0018] The injection device includes: a PSMA probe, a probe storage bottle, and a syringe, wherein the PSMA probe is stored in the probe storage bottle.

[0019] In particular, the probe storage bottle is a sterile, heat-free negative pressure bottle. The syringe is a disposable sterile syringe.

[0020] The prepared fluorescent radionuclide dual-modal PSMA probe is placed in a sterile, pyrogen-free "negative pressure bottle" or probe storage bottle (Atom High-Tech Co., Ltd., 10ml negative pressure bottle), and is drawn by a nurse using a "disposable sterile syringe" (Shandong Weigao Group Medical Polymer Products Co., Ltd., 10ml) and then given to the patient by intravenous injection.

[0021] In particular, the near-infrared fluorescence imaging device performs specific fluorescence imaging of the tumor tissue of the patient's prostate according to the fluorescence intensity of the PAMA probe in the patient's urine.

[0022] In particular, the near-infrared fluorescence imaging device positively displays the location of the tissue by performing specific fluorescence imaging (i.e., fluorescence brightness) of the location of the tumor tissue in the prostate of the patient by the near-infrared fluorescence imaging device.

[0023] In particular, the location of the tissue positively displayed by the near-infrared fluorescence imaging device is the location of the tumor tissue of the patient's prostate that is fluorescently displayed by the near-infrared fluorescence imaging device.

[0024] In particular, fluorescently highlighting the location of the tumor tissue in the patient's prostate preferably uses green fluorescence to image the location of the tumor tissue in the patient's prostate.

[0025] In particular, the fluorescent imaging (fluorescent brightening) preferably adopts green fluorescent imaging (green fluorescent brightening).

[0026] In particular, the near-infrared fluorescence imaging device performs fluorescence imaging of the tumor tissue in the patient's prostate based on the fluorescence intensity of the PAMA probe in the patient's urine, which means that when the fluorescence intensity of the PAMA probe in the patient's urine decays by ≥90%, the fluorescence-positive imaging of the tumor tissue in the patient's prostate is performed, that is, the tumor tissue in the patient's prostate is fluorescently brightened.

[0027] In particular, the near-infrared fluorescence imaging device detects the fluorescence intensity of the PAMA probe in the patient's urine and calculates the attenuation of the fluorescence intensity of the PAMA probe in the patient's urine.

[0028] In particular, after the PAMA probe is injected into the patient using an injection device, timing is started from the end of the injection, and the fluorescence intensity of the PAMA probe in the patient's urine is detected using a near-infrared fluorescence imaging device 2 hours after the injection; and timing is started from the end of the injection, and the fluorescence intensity of the PAMA probe in the patient's urine is detected every 4 hours using a near-infrared fluorescence imaging device; and the attenuation of the fluorescence intensity of the PAMA probe in the patient's urine relative to the fluorescence intensity 2 hours after the injection is calculated.

[0029] In particular, the PSMA probe is a PSMA targeting nuclide / fluorescence dual-modal ligand represented by the structural formula (2) labeled with a radionuclide.

[0030]

[0031] Among them, in formula (2), n=1, 2, 3, 4, preferably n=3.

[0032] In particular, the radionuclide is 68 Ga, 64 Cu, 18 F. 86 Y. 90 Y. 89 Zr, 111 In, 99m Tc, 11 C. 123 I. 125 I or 124 I, preferably 68 Ga.

[0033] The binding skeleton "ODAP-Urea" of the dual-modal PSMA probe used in the therapeutic device of the present invention has a binding ability targeting PSMA that is comparable to the binding skeleton Glu-Urea of ​​the existing known dual-modal probe targeting PSMA derived from Glu-Urea inhibitor, and is more hydrophilic, which helps to balance the high hydrophobicity of cyanine dyes.

[0034] Dual-mode PSMA probe used in this treatment device 68 The uptake of Ga-P1-P4 in the tumor area was significantly higher than that in other non-target areas, especially 68 Ga-P3 has good metabolic kinetics. In near-infrared zone I optical imaging, it can be specifically concentrated in the tumor area. The uptake in the tumor area reaches a peak at 2 hours. After 4 hours, the tumor area and surrounding tissues can be clearly distinguished. After 24 hours, accurate biodistribution data in major organs are displayed, which is consistent with the PET imaging results at early time points. It can be used for preoperative PET imaging and intraoperative near-infrared zone I fluorescence navigation.

[0035] Animal experiments show that the dual-mode PSMA probe used in the therapeutic device of the present invention 68 Ga-P1~P4 are highly safe. In the acute toxicity experiment on normal mice, there was basically no difference in the body weight of mice in the experimental group and the normal control group. There was no significant difference in the expression levels of AST, ALT and BUN in the serum of the two groups of mice. The H&E staining results also showed no obvious pathological abnormalities in the main organs (heart, liver, spleen, lung, and kidney).

[0036] Particularly, the amount of radionuclide in the PSMA probe is (0.05-0.1) mCi / kg, preferably 0.1 mCi / kg.

[0037] Particularly, the injection dose of the PSMA probe injected into the patient's body using the injection device is (0.004-0.04) mg / kg, preferably 0.04 mg / kg.

[0038] In particular, the near-infrared fluorescence imaging device selects the Firefly imaging system of the da Vinci surgical robot and the fluorescence imaging module of the fluorescence laparoscope.

[0039] In particular, the fluorescence imaging module of the fluorescence laparoscope is the Huanuokang fluorescence laparoscope system.

[0040] In particular, the near-infrared fluorescence imaging device is a fluorescence imaging function with a built-in "Firefly" The integrated technology of [Intuitive Surgical, Sunnyvale, CA, USA] and the Da Vinci robotic platform [Intuitive Surgical, Sunnyvale, CA, USA].

[0041] In particular, the surgical robot for removing tumor tissue from the patient's prostate is a laparoscopic surgical robot, preferably a da Vinci surgical robot system or a Condor surgical robot system.

[0042] Compared with the prior art, the therapeutic device of the present invention has the following advantages:

[0043] 1. When the treatment device of the present invention is used for radical prostatectomy, the postoperative positive rate of resection margin is significantly low, and the positive rate of resection margin is ≤18.8%;

[0044] 2. When using the therapeutic device of the present invention to perform radical prostatectomy, the tumor tissue can be accurately removed under the guidance of fluorescence navigation during the operation, and the tumor tissue can be removed completely; if there is a positive surgical margin, the near-infrared fluorescence imaging device of the therapeutic device of the present invention can be used to perform real-time fluorescence imaging (i.e., fluorescent highlighting) of the tumor tissue, and residual tumor tissue can be found, so that the tumor can be removed as completely and completely as possible, the positive margin rate can be reduced, the risk of biochemical recurrence of patients after surgery can be reduced, and the patient's prognosis can be improved.

[0045] 3. Since the neurovascular bundle is closely related to the prostate and urethra, the use of the treatment device of the present invention can help the surgeon to determine whether there is any tumor residue around the neurovascular bundle, improve the success rate of neurovascular bundle preservation, and only remove the tumor tissue that is fluorescently imaged, thereby reducing the risk of various complications such as postoperative erectile dysfunction and urinary incontinence caused by neurovascular bundle damage, significantly reducing the impact on the patient's postoperative quality of life, and improving the quality of life of postoperative patients.

[0046] 4. The treatment equipment of the present invention is used to detect the general position of the patient's prostate tumor with a PET / CT imaging device, and a near-infrared fluorescence imaging device is used to perform fluorescence imaging of the tumor tissue during the operation, accurately locate the location of the tumor tissue, clearly define the boundary between the tumor tissue and normal tissue, and clearly distinguish the tumor tissue from the normal tissue of the prostate. This is beneficial in the process of removing the tumor tissue, completely removing the tumor tissue without destroying the normal tissue, and without injuring the adjacent nerves and blood vessels, which significantly reduces the risk of accidentally injuring the surrounding blood vessels and nerves during the operation, and improves the safety of the operation.

[0047] 5. During the operation, the surgeon can operate the surgical robot of the treatment device of the present invention with extremely high precision to perform delicate operations and accurately remove the tumor; and the surgical robot has high stability, which improves the success rate of the operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 is a schematic diagram of the structure of the therapeutic device of the present invention;

[0049] Figure 1A Tumor tissue fluorescence imaging site 68 PET imaging results of Ga-P3;

[0050] Figure 1B Tumor tissue fluorescence imaging site 68 CT imaging results of Ga-P3;

[0051] Figure 2 A near-infrared fluorescence imaging device is used to fluorescently image tumor tissue during RP surgery. DETAILED DESCRIPTION

[0052] The present invention is further described in detail below in conjunction with the embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention. However, the embodiments of the present invention are not limited thereto.

[0053] like Figure 1The therapeutic device for reducing the positive resection margin after radical prostatectomy of the present invention comprises: an injection device, a PET / CT imaging device, a near-infrared fluorescence imaging device and a surgical robot used in sequence, wherein:

[0054] An injection device is used to inject a PSMA-targeted radionuclide / fluorescent dual-modal molecular probe (PSMA probe for short) into a patient's body, that is, the PSMA-targeted radionuclide / fluorescent dual-modal molecular probe is administered to a patient who is to undergo radical prostatectomy by intravenous injection;

[0055] The injection device of the present invention is an isotope injection device, that is, an injection device for injecting a radioactively labeled tracer (i.e., a PSMA probe) into a patient, comprising: a PSMA probe, a probe storage bottle, and a syringe, wherein the syringe is a disposable sterile syringe.

[0056] The prepared fluorescent radionuclide dual-modal PSMA probe is placed in a sterile, pyrogen-free "negative pressure bottle" or probe storage bottle (Atom High-Tech Co., Ltd., 10ml negative pressure bottle), and is drawn by a nurse using a "disposable sterile syringe" (Shandong Weigao Group Medical Polymer Products Co., Ltd., 10ml) and then given to the patient by intravenous injection.

[0057] The PSMA probes are: 68 The chelate of Ga and the ligand shown in structural formula (2) is a prostate cancer nucleic acid imaging reagent, which is prepared according to the method of the authorized patent (a PSMA targeting nuclide / fluorescence dual-modal ligand and molecular probe and application, authorization announcement number CN114014843B).

[0058] The preparation steps of the PSMA probe of the present invention are as follows:

[0059] (i) First, a bimodal ligand (ODAP-PSMA targeting bimodal ligand) is synthesized; the structural formula of the ligand is shown in formula (2), wherein n=1, 2, 3, 4.

[0060] All reagents were purchased from reagent companies without purification, and the coupling of amino acids was carried out according to the standard Fmoc solid phase synthesis method.

[0061] Reaction conditions: (a) triphosgene, triethylamine, anhydrous DCM; (b) triethylamine, anhydrous DCM; (c) Pd / C, H2, methanol; (d) NaHCO3, dioxane, water; (e) N,N-diisopropylethylamine, 2-chlorotrityl resin, DCM, DMF; (f) 20% piperidine in DMF, Fmoc-3-(2-naphthyl)-L-alanine, HBTU, HOBt and DIPEA in DMF; (g) 20% piperidine in DMF, Fmoc-(4-aminomethyl)benzoic acid, HBTU, HOBt and DIPEA in DMF; (h) 20% piperidine in DMF solution, DDE-Fmoc-L-lysine, HBTU, HOBt and DIPEA in DMF solution; (i) 20% piperidine in DMF solution, DOTA, HBTU, HOBt and DIPEA in DMF solution; (j) 2% hydrazine in DMF solution, Fmoc-L-aspartic acid-1-tert-butyl ester, HBTU, HOBt and DIPEA in DMF solution; (k) 20% piperidine in DMF solution, LY-12, PyBOP and DIPEA in DMF solution; (l) trifluoroacetic acid, water and triisopropylsilane. All raw materials used are commercially available or prepared by conventional organic synthesis methods.

[0062] Take 100 mg of resin (0.03 mmol) in a 10 mL solid phase synthesis tube, add 2 mL of dichloromethane (DCM) to swell, repeat three times, 5 minutes each time, then wash with N, N-dimethylformamide (DMF) three times, 5 minutes each time. Use DMF solution containing 20% ​​piperidine (v / v) to remove the amino protecting group Fmoc. The specific operation is to react with 2 mL of 20% piperidine in DMF solution for 2 minutes, 10 minutes, and 10 minutes, and then use 2 mL DMF to wash 3-5 times, 2 minutes each time. Relative to the resin (0.03 mmol), 3 times the chemical amount of Fmoc amino acid is activated by 3.6 times the chemical amount of HBTU or PyBOP in the presence of 7.2 times the chemical amount of DIPEA and added to the synthesis tube, and reacted for 1 hour under electromagnetic stirring. Except for the step of removing the amino protecting group Dde, all deprotection, activation and coupling steps are carried out according to the above method. The amino protecting group Dde was removed using a DMF solution containing 2% hydrazine (v / v), and the specific operation was 2mL of 2% hydrazine in DMF solution was reacted for 2 minutes, 3 minutes, and 3 minutes. The ligand was dissociated from the resin and the tert-butyl ester was removed using 5mL of trifluoroacetic acid / triisopropylsilane / water (95:2.5:2.5, v / v / v) with stirring for 2 hours, and the resin was washed with 2mL of trifluoroacetic acid, and all filtrates were collected. After removing the trifluoroacetic acid under reduced pressure, the crude product was prepared by reverse phase HPLC and freeze-dried to obtain the target ligand.

[0063] (II) Nuclide labeling

[0064] 68 Ga: Accurately weigh 1.0 mg of ligand into a sample tube, add 200 μL DMSO (dimethyl sulfoxide) to dissolve it, and dilute the ligand concentration to 5 μg / μL. Pipette 6 μL of ligand solution and 130 μL NaOAc solution (1 mol / L) into a vial, and add 2 mL of freshly washed 68 Ga 3+ Ion solution (solvent is 0.05 mol / L hydrochloric acid solution, radioactivity is 10-17 mCi), shake well and seal, react at 90°C for 10 minutes. The reaction solution is cooled to room temperature.

[0065] The PSMA probe used in the therapeutic device of the present invention is prepared according to the invention patent with the authorization announcement number CN114014843B 68 The concentration ratio of Ga is (0.01-0.1) / 0.1 mCi / kg; the injection dose of PSMA probe is (0.004-0.040) mg / kg.

[0066]

[0067] In formula (1), n=1, 2, 3, 4.

[0068] In a specific embodiment, the PSMA probe ligand n=3, and the radioactive element is 68 Ga, referred to as 68 Ga-P3.

[0069] PET / CT imaging device, a detection device for displaying the general location of a prostate tumor in a patient injected with a PSMA probe, that is, for imaging the head and trunk of a patient injected with a PSMA probe who is to undergo radical prostatectomy, to determine the general location of the patient's prostate tumor;

[0070] The PET / CT imaging device includes: PET detector, CT scanner, PET and CT fusion system, data acquisition system, image reconstruction and processing computer, control panel and operating system, patient bed, isotope injection device, and auxiliary support system; among which:

[0071] PET detectors, also known as PET modules, are used to detect positrons (or gamma rays) emitted from radioactive isotopes injected into the human body.

[0072] CT scanners, which are used to perform X-ray scans of a patient's body, obtaining high-resolution images of cross sections;

[0073] PET and CT fusion system, which is used to fuse the image data from the PET detector and the CT scanner to generate a comprehensive image, so that doctors can view the overlapping information of the two scan images at the same time;

[0074] The data acquisition system is used to acquire signals from the PET detector and CT scanner and convert them into digital data; the system is responsible for signal amplification, sampling and transmission to ensure the accuracy of image quality.

[0075] Image reconstruction and processing computer, used to reconstruct and process the data collected by the data acquisition system through the computer; the processing computer converts the raw data from PET and CT into three-dimensional images, and performs data fusion to generate a comprehensive image of the patient so that doctors can make a diagnosis;

[0076] Control panel and operating system used by the operator to control various settings of the PET / CT device, the scanning process, and data storage; usually includes a touch screen interface or a computer interface for operating and monitoring the scanning process.

[0077] The patient bed, also known as the scanning bed, is used to position and fix the patient and keep the patient in the correct position during the scanning process; the bed is usually adjustable to ensure that the patient can be accurately placed in the scanning area.

[0078] Auxiliary and support systems: including power management, cooling system, emergency shutdown system, safety monitoring system, etc., to ensure the stable operation of the equipment and provide safety protection for patients and operators; detectors and other electronic components in PET / CT equipment need to maintain appropriate temperatures, and a cooling system is used to maintain stable operation of the equipment.

[0079] PET / CT examination process: The patient lies supine on the PET / CT patient bed and breathes calmly. The head and trunk acquisition conditions are: the scanning range is from the top of the head to the upper 1 / 3 of the thigh. After the tracer (PSMA probe) is injected into the patient, the patient rests and waits for about 30-120 minutes to allow the tracer to be distributed in the body.

[0080] Injection 68 PET / CT imaging is performed 2 hours after the injection of Ga-P3. The PET detector begins to capture the spatial distribution of positrons emitted by the patient's body-wide radioactive tracer and generate images, and the CT scanner is used to scan and provide high-resolution anatomical structure images. The PET and CT fusion system fuses the PET and CT image data to form a PET / CT image, which fully displays the primary lesion of prostate cancer and the location of pelvic lymph nodes, and obtains the general location of the prostate tumor in the patient injected with the PSMA probe for subsequent diagnosis. The surgeon uses the PET / CT image to roughly locate the lesion and formulate a specific plan for tumor resection surgery.

[0081] Usually injected 68 After 24±6 hours of Ga-P3, RARP was performed.

[0082] A near-infrared fluorescence imaging device is used to display the fluorescence levels of tumor tissue and normal tissue of the prostate of a patient injected with a PSMA probe; and to perform fluorescence imaging of the patient's prostate tumor tissue based on the fluorescence intensity of the PAMA probe in the patient's urine after the patient is injected with the PSMA probe, that is, to fluorescently illuminate the patient's prostate tumor tissue. In the specific implementation of the present invention, green fluorescence imaging of prostate tumor tissue is used as an example for explanation.

[0083] The near-infrared fluorescence imaging device comprises: a near-infrared light source, a probe, and a fluorescence imaging display, wherein:

[0084] Near-infrared light source: emits near-infrared light (e.g., wavelength of 750-800 nm) to excite fluorescent dyes;

[0085] Probe: used to irradiate near-infrared light into the surgical area and capture the fluorescent signal emitted from the target tissue;

[0086] Fluorescence imaging display: used to display fluorescence imaging results. The display may have multiple modes and can display different image modes (such as fluorescence only, visible light only, fused image, etc.).

[0087] The functions of the near-infrared fluorescence imaging device are as follows:

[0088] 1) Used to detect the fluorescence intensity of urine or the concentration of PSMA probes. After the injection of PSMA-targeted nuclide / fluorescence dual-modality probe (PSMA probe for short), the fluorescence intensity of PSMA probes in the patient's urine is detected every 4 hours using a near-infrared fluorescence imaging device; and the fluorescence intensity of PSMA probes in the patient's urine 2 hours after injection is detected;

[0089] 2) Based on the fluorescence intensity of the PAMA probe in the patient's urine, when the fluorescence intensity of the PAMA probe in the patient's urine decays by ≥90% relative to the fluorescence intensity 2 hours after injection, a radical resection of the patient's prostate tumor tissue is performed under the fluorescence navigation of a near-infrared fluorescence imaging device;

[0090] 3) Use a near-infrared fluorescence imaging device to perform fluorescence imaging on the patient's prostate tumor tissue. Even if the patient's prostate tumor tissue exhibits specific fluorescence (green fluorescence is used as an example in this embodiment) under the near-infrared fluorescence imaging device, the tumor tissue can be distinguished from the normal tissue of the prostate, which is beneficial for completely removing the tumor tissue during the removal of the tumor tissue without destroying the normal tissue and adjacent nerves and blood vessels, significantly reducing the risk of accidentally injuring surrounding blood vessels and nerves during surgery and reducing the positive rate of resection margins.

[0091] The near-infrared fluorescence imaging device can be the Firefly imaging system (i.e., video imaging system) of the da Vinci surgical robot or a near-infrared fluorescence laparoscope (NIR Fluorescence Laparoscope).

[0092] The near-infrared fluorescence laparoscope has the functions of a conventional laparoscope and can switch to near-infrared fluorescence mode at the same time. Through the built-in near-infrared fluorescence imaging module (including near-infrared light source, probe, and fluorescence imaging display), it can capture fluorescence signals and generate images. It can also display conventional laparoscopic images and fluorescence images at the same time, and display the fluorescence distribution of the targeted area in real time.

[0093] In a specific embodiment of the present invention, the near-infrared fluorescence imaging device is preferably the Firefly system of the da Vinci surgical robot or the Huanuokang fluorescence laparoscopic system.

[0094] Laparoscopy includes ordinary laparoscope, fluorescent laparoscope, 3D laparoscope, etc.

[0095] The fluorescent laparoscope system in the present invention is a near-infrared fluorescent laparoscope;

[0096] The da Vinci surgical robot system is equipped with a fluorescent imaging system called "Firefly"

[0097] Condor and Da Vinci are two different brands of robotic surgical systems.

[0098] Near-infrared fluorescence imaging system usage process:

[0099] 1. Use an isotope injection device to inject the PSMA probe into the patient intravenously ( 68 Ga-P3);

[0100] 2. Use a near-infrared fluorescence imaging device to detect the fluorescence intensity of the PSMA probe in the urine of patients 2 hours after injection of the PSMA probe and to detect the fluorescence intensity of the PSMA probe in the urine of patients every 4 hours after the injection; wherein: when the fluorescence intensity of the PAMA probe in the patient's urine decays by ≥90% relative to the fluorescence intensity 2 hours after injection, perform RARP surgery on the patient;

[0101] 3. During the operation, a near-infrared fluorescence imaging device is used to perform fluorescence imaging of the patient's prostate tumor tissue (i.e., fluorescently illuminate / display the tumor tissue, and in the embodiment of the present invention, the tumor tissue is illuminated with green fluorescence); and the location of the tumor tissue is accurately displayed, and the boundary and limit between the tumor tissue and normal tissue are clearly displayed;

[0102] During the operation, the near-infrared light source of the near-infrared fluorescence imaging device emits near-infrared light of a specific wavelength, which is irradiated into the internal body area, activates the PSMA probe injected into the body, and fluorescently images the tumor tissue.

[0103] The activated fluorescent dye in the PSMA probe emits a fluorescent signal of a specific wavelength, which is captured by the fluorescent imaging module of the near-infrared fluorescent imaging device through the probe of the laparoscope. The imaging system of the near-infrared fluorescent laparoscope displays ordinary visible light images and fluorescent images at the same time, and usually uses image fusion technology to synthesize and display the two images. In this way, surgeons can see the difference between normal tissue and the targeted area containing fluorescent dye (prostate cancer tissue).

[0104] 4. During the operation, the surgeon performs precise surgical operations based on the information (fluorescence and the location of fluorescence) displayed by the near-infrared fluorescence imaging device (such as the Firefly system of the da Vinci surgical robot and the fluorescence laparoscopic system), completely removing the prostate and prostate tumors while minimizing damage to the surrounding structures of the prostate.

[0105] The surgical robot is used to remove the tumor tissue of the patient's prostate according to the general position of the patient's prostate tumor displayed by a PET / CT imaging device and the tumor tissue of the patient's prostate as fluorescently imaged (i.e., bright fluorescence, such as bright green fluorescence) by a near-infrared fluorescence imaging device and the precise position of the tumor tissue, i.e., to perform standardized transperitoneal RARP (robot-assisted radical prostatectomy); according to the range of the fluorescence-positive area, the range and size of the prostate tumor tissue are determined, and the prostate and the tumor tissue in the fluorescence-positive area are completely removed.

[0106] The fluorescence positive area is the tissue area of ​​fluorescence imaging, and in this embodiment, green fluorescence imaging is used for illustration, that is, the green fluorescence display area is the fluorescence positive area.

[0107] The surgical robot is an endoscopic surgical control system. The surgical robot device is a laparoscopic surgical robot, such as the da Vinci Xi (Intuitive Surgical, Sunnyvale, CA, USA, a pioneer in minimally invasive surgical instruments and technologies in the United States) and the Condo surgical robot (Suzhou Condo Robotics Co., Ltd., Suzhou, China).

[0108] The laparoscopic surgical robot includes: a robot console, a surgical robotic arm system and a video imaging system.

[0109] Surgical robots usually have multiple mechanical arms (usually 3-4), each of which can accurately operate different tools, such as cameras and various surgical instruments. The movements of the robotic arms are very flexible and can simulate the movements of the surgeon's hands, even surpassing the flexibility and stability of the hands, avoiding the tremors of the hands in traditional surgery.

[0110] The surgeon operates in front of the console and controls the robot to perform surgery through the console's controller. The console provides a 3D high-definition view and can precisely control the robot's arms and tools through two-hand controllers and foot pedals. Through high-precision hand movements, doctors can perform delicate operations.

[0111] The da Vinci surgical robot used in the specific implementation of the present invention is also called an "endoscopic surgery control system", which consists of three parts: a surgeon's console, a bedside robotic arm system, and a video imaging system. The surgeon sits in front of the surgeon's console, observes the surgical field in a stereoscopic eyepiece, and performs the surgery by remotely controlling the bedside robotic arm and lens through a controller, which can achieve precise synchronization between the surgical instrument and the surgeon's hands.

[0112] The process of using the robot:

[0113] At the beginning of the operation, the surgeon obtains a 3D high-definition view of the surgical field through the display on the robot console, which provides a clearer and magnified view than traditional laparoscopes. The surgeon uses the joysticks and foot pedals on the console to precisely control each arm of the robot to perform specific operations. The arms can perform complex movements like human hands, such as rotating, grasping, and cutting. At the beginning of the operation, one arm may be responsible for operating the laparoscope camera, while the other arm is used to operate the surgical instruments. The flexibility of the robotic arms far exceeds that of traditional surgical methods, making it easier to enter hard-to-reach body cavities or anatomical areas.

[0114] Robotic manipulation of the therapeutic device using the present invention has the following advantages and benefits:

[0115] Precision operation: With the assistance of robotic systems, surgeons can operate with extremely high precision. For example, when performing tumor resection, robots can help doctors precisely remove the tumor while minimizing damage to surrounding normal tissue.

[0116] High stability: The robotic system can reduce the slight vibration of the doctor's hands and ensure the stability of surgical operations, especially during delicate operations.

[0117] The working principle of the therapeutic device for reducing positive resection margin after radical prostatectomy of the present invention is as follows:

[0118] 1. Prepare PSMA probes according to the method of the authorized patent (A PSMA-targeted nuclide / fluorescence dual-modal ligand and molecular probe and application, authorization announcement number CN114014843B). The PSMA probes in the specific embodiments of the present invention are selected to have qualified quality control. 68 Ga-P3 (0.05-0.1 mCi / kg).

[0119] 2. According to the weight (kg) of the patient to be treated with radical prostatectomy, the injection dose of PSMA probe is (0.004-0.020) mg / kg. Use the disposable sterile syringe of the injection device to accurately draw the injection amount of PSMA probe. 68 Ga-P3 (0.05-0.1 mCi / kg) is injected intravenously into the patient. For example, if the patient weighs 70 kg, the PSMA probe is injected 68 The amount of Ga-P3 is 70×0.01=0.7 mg.

[0120] 3. For injection 68 Ga-P3 (0.05-0.1mCi / kg) was administered 0.5 hour, 1 hour, and 2 hours later. The patient's head and trunk were imaged using a PET / CT imaging device, with the scanning range ranging from the top of the head to the upper 1 / 3 of the thigh. The patient was placed in a supine position, lying flat on the PET / CT examination bed, and breathing calmly. The acquisition conditions for the head and trunk were the same as above. The data were reconstructed using the OSEM method to obtain coronal, sagittal, and transverse PET / CT fusion images, which fully displayed the primary lesions of prostate cancer and the location of pelvic lymph nodes. The PET / CT parameters were obtained in the MedEx MEMRS V8.0 software.

[0121] injection 68 After 2 hours with Ga-P3 probe, the PET / CT imaging effect is clear, and the radionuclide localization of prostate cancer lesions can be obtained, and the approximate location of the patient's prostate tumor tissue can be obtained, retained and recorded, such as Figure 1A , 1B .

[0122] 4. After the injection of the PSMA probe, start timing from the end of the injection and use a near-infrared fluorescence imaging device to measure the fluorescence intensity of the PSMA probe in the patient's urine 2 hours after the injection; and

[0123] Starting from the end of the injection, the fluorescence intensity of the PSMA probe in the patient's urine is detected every 4 hours (usually 2-8 hours) using a near-infrared fluorescence imaging device until the fluorescence intensity of the PSMA probe in the urine is attenuated by more than 90% relative to the fluorescence intensity of the PSMA probe in the patient's urine 2 hours after the injection, and radical prostatectomy is prepared.

[0124] The fluorescence intensity attenuation of the PSMA probe in the patient's urine was detected by a near-infrared fluorescence imaging device to avoid contamination of the surgical area by residual PSMA probe in the patient's urine during RARP.

[0125] 5. Use a surgical robot to perform standardized transperitoneal RARP on patients, usually after injection. 68 At 24±6h after Ga-P3 (depending on the patient's constitution, the metabolic rate of the PSMA probe in the body is different), the surgical robot performs RARP.

[0126] The surgical robot device used was the da Vinci Si / Xi surgical system (Intuitive Surgical, Sunnyvale, CA, USA).

[0127] According to the standardized fluorescence navigation surgical process, the Firefly fluorescence system (near-infrared fluorescence imaging device) of the da Vinci Si / Xi surgical system of the surgical robot device was used to observe the region of interest (i.e., various surfaces of the prostate and the surgical wound after surgical resection) at a distance of approximately 4 cm, and the surgical process was recorded by video.

[0128] The specific procedures of fluorescence navigation surgery are as follows:

[0129] First, the prostate and pelvic lymph nodes were explored under fluorescence mode; the near-infrared fluorescence imaging device displayed the fluorescence imaging results of prostate tumor tissue, such as Figure 2 ;

[0130] The surgical robot uses the near-infrared fluorescence imaging device to perform fluorescence imaging on the green fluorescent bright area of ​​the patient's prostate during radical prostatectomy. Figure 2 shown. Figure 2 The middle dotted area is the precise location of the tumor tissue imaged by the near-infrared fluorescence imaging device.

[0131] Afterwards, RP (radical prostatectomy) was started under fluorescent navigation. Before opening the bladder neck, the bladder was flushed through the urethra to further reduce the residual probe in the bladder to avoid PSMA probe in urine ( 68 Ga-P3) residues contaminate the surgical area; after opening the bladder neck, use the fluorescence mode to observe the prostate and bladder neck;

[0132] Then, the prostate and prostate tumor were completely removed under fluorescence navigation. After the resection, the prostate margins were observed. The fluorescence-positive areas at each margin were observed to see if they were still fluorescent. The surgery area was observed to see if there was any residual fluorescence. The surgery was terminated after no residual fluorescence was observed. The video fully recorded the surgery process.

[0133] Finally, biological dyes are used to mark the prostate fluorescence-positive areas after surgery to facilitate identification of the fluorescence-positive areas during tissue pathological analysis.

[0134] The decision on whether to perform e-PLND (extended pelvic lymph node dissection) is based on the patient's risk classification, preoperative imaging examinations and the patient's own wishes. For patients who need e-PLND, surgeons operate surgical robots to perform standardized e-PLND, use near-infrared fluorescence imaging devices to observe whether each lymph node area has fluorescence imaging, remove fluorescence-positive lymph nodes and send them separately for histopathological analysis.

[0135] 6. Perform histopathological analysis on the tissue removed by radical prostatectomy.

[0136] Prostate and lymph node tissue sections were paraffin-embedded to obtain thin tissue sections. Tumor-positive or fluorescent prostate and LN tissue blocks were sliced ​​three times in a row: one H&E-stained section for tumor assessment, which was used as the gold standard for tumor detection; one PSMA immunohistochemical staining to evaluate PSMA overexpression; and one PSMA immunofluorescence staining. The consistency of H&E staining, PSMA immunohistochemical staining, and immunofluorescence staining was observed.

[0137] Prospective single-arm clinical study in humans using the therapeutic device of the present invention using a PSMA probe 68 Ga-P3 is used for preoperative imaging and intraoperative navigation of prostate cancer. 16 patients with intermediate- and high-risk limited-stage or locally advanced prostate cancer were enrolled and injected intravenously with different doses of 68 Ga-P3 (0.004 mg / kg in 6 cases, 0.010 mg / kg in 5 cases, and 0.020 mg / kg in 5 cases) was administered with PET / CT imaging at 0.5 h, 1 h, and 2 h after drug injection for preoperative staging of prostate cancer. 68 After the fluorescence intensity in the patient's urine after Ga-P3 decayed by ≥90% relative to the fluorescence intensity in the patient's urine 2 hours after injection, RARP+e-PLND under fluorescence navigation was performed, and the fluorescence-positive area was marked for tissue pathological analysis.

[0138] All patients did not have any 68 Adverse reactions related to Ga-P3 or intraoperative fluorescence navigation. Histopathological analysis showed that all fluorescence-positive areas were tumor remnants or tumors close to the resection margin. The PSM (positive surgical margin) rate of RARP under fluorescence navigation was 18.8%, which was significantly lower than the existing positive surgical margin rate after radical prostatectomy.

[0139] Therefore, by using the treatment device of the present invention in preoperative PET imaging and intraoperative fluorescence navigation for prostate cancer, the safety and effectiveness of RARP surgery are significantly improved.

[0140] The above embodiments of the present invention are only exemplary and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

Claims

1. A therapeutic device for reducing positive resection margins after radical prostatectomy, characterized in that: include: An injection device for injecting a PSMA-targeted radionuclide / fluorescence dual-modality molecular probe, i.e., a PSMA probe, into a patient's body; A PET / CT imaging device for showing the general location of a prostate tumor in a patient injected with a PSMA probe; An intraoperative near-infrared fluorescence imaging device for displaying the fluorescence levels of tumor tissue and normal tissue in the prostate of a patient injected with a PSMA probe; A surgical robot for completely removing the prostate and tumor tissue of a patient according to the general location of the patient's prostate tumor displayed by a PET / CT imaging device and the location of the tissue positively displayed by an intraoperative near-infrared fluorescence imaging device; Wherein, the near-infrared fluorescence imaging device performs fluorescence imaging of the tumor tissue of the patient's prostate according to the fluorescence intensity of the PAMA probe in the patient's urine.

2. The therapeutic device according to claim 1, characterized in that The near-infrared fluorescence imaging device performs fluorescence imaging of the tumor tissue of the patient's prostate according to the fluorescence intensity of the PAMA probe in the patient's urine, which means that when the fluorescence intensity of the PAMA probe in the patient's urine decays by ≥90%, the fluorescence-positive imaging of the tumor tissue of the patient's prostate is performed, that is, the tumor tissue of the patient's prostate is fluorescently brightened.

3. The therapeutic device according to claim 1 or 2, characterized in that: The near-infrared fluorescence imaging device detects the fluorescence intensity of the PAMA probe in the patient's urine and calculates the attenuation of the fluorescence intensity of the PAMA probe in the patient's urine.

4. The therapeutic device according to claim 1 or 2, characterized in that: The PSMA probe is a PSMA targeting nuclide / fluorescence dual-modal ligand represented by the structural formula (2) labeled with a radionuclide. Among them, in formula (2), n=1, 2, 3, 4, preferably n=3.

5. The therapeutic device according to claim 4, characterized in that The radionuclide is 68 Ga, 64 Cu, 18 F. 86 Y. 90 Y. 89 Zr, 111 In, 99m Tc, 11 C. 123 I. 125 I or 124 I, preferably 68 Ga.

6. The therapeutic device according to claim 4, characterized in that: The dosage of the radionuclide in the PSMA probe is (0.05-0.1) mCi / kg, preferably 0.1 mCi / kg.

7. The therapeutic device according to claim 1 or 2, characterized in that: The injection dose of the PSMA probe injected into the patient's body using the injection device is (0.004-0.04) mg / kg, preferably 0.04 mg / kg.

8. The therapeutic device according to claim 1 or 2, characterized in that: The near-infrared fluorescence imaging device is selected from the Firefly imaging system of the da Vinci surgical robot and the fluorescence imaging module of the fluorescence laparoscope.

9. The therapeutic device according to claim 1 or 2, characterized in that: The surgical robot for removing the tumor tissue of the patient's prostate is a laparoscopic surgical robot, preferably a da Vinci surgical robot or a Condor surgical robot.

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