A therapeutic device for reducing positive surgical margins after radical prostatectomy

Abstract

The application discloses a kind of treatment equipment for reducing postoperative positive margin of prostate radical resection, including injection device for injecting PSMA probe into body, PET / CT imaging device, near-infrared fluorescence imaging device and surgical robot, near-infrared fluorescence imaging device shows the fluorescence level of tumor tissue and normal tissue of the prostate of the patient injected with probe, and prostate tumor tissue is fluorescently imaged according to the fluorescence intensity of probe in urine.The treatment equipment of the application carries out fluorescent imaging on tumor tissue during resection, and accurately positions, and the tumor tissue is accurately resected under the fluorescence navigation of surgical robot, and postoperative positive margin rate is significantly reduced;After prostate radical resection is carried out using the treatment equipment of the application, the risk of biochemical recurrence of patient is significantly reduced and prognosis is good;Moreover, it can also avoid the complications such as erectile dysfunction, urinary incontinence, urethral stricture caused by intraoperative damage to nerve and vascular bundle, and significantly reduce the influence on the quality of life of patient after operation.

Description

Technical Field

[0001] This invention relates to a treatment device for prostatectomy, and more particularly to a treatment device for reducing positive surgical margins after radical prostatectomy, belonging to the field of medical devices. Background Technology

[0002] In recent years, surgical robotic systems, with their high-definition magnified three-dimensional vision and more flexible robotic arms, have made robot-assisted radical prostatectomy (RARP) the mainstream surgical treatment for prostate cancer. RARP can significantly improve surgical precision and has significant advantages in short-term urinary continence, sexual function, and short-term complications, while achieving the same oncological outcomes as traditional open surgery.

[0003] The key to successful RARP lies in the complete removal of tumor tissue while preserving surrounding vital functional structures to the greatest extent possible. To achieve both goals simultaneously, accurate intraoperative tumor boundary identification is crucial. Rapid advancements in prostate cancer-specific imaging techniques have significantly improved the accuracy of prostate cancer diagnosis and staging. However, surgeons still primarily rely on their own experience, combined with limited visual information such as color, texture, and shape, as well as tactile information such as firmness or surface smoothness, to differentiate between cancerous and non-cancerous tissues. This subjective judgment method has a high rate of positive surgical margin (PSM), currently ranging from 6-50% in RP. PSM increases the risk of postoperative biochemical recurrence, impacting patient prognosis.

[0004] In recent years, near-infrared fluorescence intraoperative navigation technology has opened up new avenues for the precision treatment of prostate cancer. During RARP (Rapid Reversal of Prostate Cancer) surgery, 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. This effectively distinguished the prostate from surrounding neurovascular bundles, vas deferens, and other structures, and also effectively differentiated lymph nodes from adjacent nerves and blood vessels, significantly reducing the risk of accidental injury to surrounding blood vessels and nerves during surgery. However, due to the non-tumor specificity of ICG, it cannot specifically distinguish between lymph nodes with tumor metastases and normal lymph nodes, nor can it differentiate between tumor tissue and normal tissue in 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 (100-1000-fold) on the surface of 90% of prostate cancer cells, and its expression level is closely related to tumor invasion and malignancy stage. This target is an ideal biomarker for precise localization imaging of prostate cancer lesions, used in radionuclide imaging and radioligand therapy. Fluorescent probes targeting PSMA generally consist of three parts: a PSMA targeting group, a spacer group, and a fluorophore. The targeting group is usually a small molecule inhibitor of PSMA, ensuring high affinity for the PSMA protein. The fluorophore often uses near-infrared fluorescent dyes, such as indocyanine green, IRDye800RS, IRDye800CW, Cy7, Cy5.5, and their derivatives. By combining near-infrared dyes with the PSMA targeting group, a series of fluorescent probes targeting PSMA are synthesized, thereby achieving real-time fluorescence imaging of PSMA-positive lesions during surgery. Fluorescent probes targeting PSMA have high affinity for the PSMA protein, enabling specific fluorescence imaging in tumors.

[0006] Existing PSMA-targeting probes are divided into single-modal near-infrared fluorescence probes and radionuclide / fluorescence dual-modal molecular imaging probes. However, single-modal near-infrared fluorescence probes are limited by their penetration depth, making it difficult to identify deeper tumor lesions. For patients scheduled to receive PSMA-targeted near-infrared fluorescence probe intraoperative navigation, a waiting period is required after PSMA PET / CT to allow the radionuclide imaging probe to clear before the fluorescence probe can be injected for surgical navigation, affecting the patient's treatment timing. Dual-modal molecular imaging probes, by integrating infrared fluorescent dyes and radioactive isotopes into a single ligand, overcome the limitations of single imaging technologies, achieving the dual functions of preoperative whole-body functional imaging and precise intraoperative fluorescence navigation. In the diagnosis and treatment of prostate cancer, dual-modal probes can not only effectively assess tumor staging through preoperative PET / CT or PET / MRI imaging, but also accurately identify tumor boundaries during surgery using fluorescence imaging technology, reflecting lesion size, invasion range, and lymph node metastasis in real time and intuitively, providing important evidence for clinical decision-making.

[0007] Currently, several fluorescent probes targeting PSMA have been developed, including: 1) Probes OTL78 and IS-002, derived from glutamate-urea (Glu-Urea) inhibitors, have undergone clinical trials; these clinical trials have preliminarily verified the good safety of PSMA-targeting fluorescent probes OTL78 and IS-002 in humans. With the help of these probes and near-infrared fluorescence imaging technology, the PSM rate can be reduced, the accuracy of lymph node dissection can be improved, and better treatment results can be brought to patients; 2) PSMA probes based on ODAP-Urea have high tumor uptake, their in vivo metabolism is comparable to existing PSMA probes, and they have high safety in vivo with no drug-related adverse reactions; moreover, PSMA nuclide / fluorescent dual-modal probes based on ODAP-Urea have low radioactivity concentration in the bladder, which can not only locate and characterize metastatic lesions, but also show good performance in the precise location and staging of lesions inside the prostate in early prostate cancer patients. It is a very promising PSMA-targeting positron-emitting molecular probe.

[0008] The PSMA probe used in the treatment device for reducing positive surgical margins after radical prostatectomy of the present invention is derived from an ODAP-Urea inhibitor, with DOTA as a radionuclide chelating agent and indocyanine green derivative as a fluorophore. The metabolic kinetics of the probe are optimized by a linker modified with carboxylic acid. Based on the molecular P137 with the structural formula as shown in formula (1), four PSMA-targeted radionuclide fluorescent dual-modality molecular imaging probes P1-P4 based on the ODAP-Urea backbone are designed and synthesized, as shown in formula (2).

[0009]

[0010] Equation (1)

[0011]

[0012] Equation (2)

[0013] In equation (2), n = 1, 2, 3, 4.

[0014] Previous research by our research group has revealed a dual-modal PSMA probe. 68 Ga-P1-P4 exhibits significantly higher uptake in tumor regions than in other non-target regions, and in near-infrared I region optical imaging, it can specifically concentrate in the tumor region. Therefore, this invention utilizes a dual-modal PSMA probe in its treatment device. After injection of the dual-modal probe, its fluorescence imaging (brightening of tumor tissue) can clearly distinguish the tumor region from surrounding tissues. Combined with PET imaging results, this is used for near-infrared I region fluorescence navigation in radical prostatectomy. Summary of the Invention

[0015] The purpose of this invention is to address the technical problems of existing devices or apparatuses for radical prostatectomy, such as difficulty in distinguishing tumor tissue from non-tumor tissue during surgery and a high positive rate of surgical margins. This invention provides a treatment device that reduces the positive rate of surgical margins after radical prostatectomy. During treatment, this device can achieve preoperative PET imaging using a PSMA-targeting radionuclide fluorescence dual-modal probe to clearly identify the location of the tumor lesion, and use intraoperative near-infrared fluorescence imaging to delineate the tumor tissue boundary in real time, accurately locating and defining the tumor tissue boundary, thereby reducing the positive rate of surgical margins in radical prostatectomy and minimizing the risk of postoperative tumor residue.

[0016] To achieve the objectives of this invention, one aspect of this invention provides a treatment device for reducing positive surgical margins after radical prostatectomy, comprising:

[0017] An injection device for injecting PSMA-targeted nuclide / fluorescent dual-modal molecular probes, i.e., PSMA probes, into patients.

[0018] A PET / CT imaging device used to display the gross location of prostate tumors in patients who have been injected with PSMA probes;

[0019] 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.

[0020] A surgical robot used to completely remove the patient's prostate and tumor tissue based on the gross location of the patient's prostate tumor as shown by a PET / CT imaging device and the location of the tissue as shown by a positive intraoperative near-infrared fluorescence imaging device;

[0021] 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.

[0022] In particular, the probe storage bottle is a sterile, pyrogen-free negative pressure bottle. The syringe is a disposable sterile syringe.

[0023] The prepared fluorescent nuclide dual-modal PSMA probe was placed in a sterile, pyrogen-free "negative pressure bottle," i.e., a probe storage bottle (Atomic High-Tech Co., Ltd., 10ml negative pressure bottle). The nurse then used a "disposable sterile syringe" (Shandong Weigao Group Medical Polymer Products Co., Ltd., 10ml) to draw it out and administer it to the patient intravenously.

[0024] In particular, the near-infrared fluorescence imaging device performs specific fluorescence imaging of tumor tissue in the patient's prostate based on the fluorescence intensity of the PAMA probe in the patient's urine.

[0025] In particular, the positive display of the location of the near-infrared fluorescence imaging device is a specific fluorescence imaging (i.e. fluorescence brightening) of the tumor tissue in the patient's prostate by the near-infrared fluorescence imaging device.

[0026] In particular, the location of the positively displayed tissue by the near-infrared fluorescence imaging device is the location of the tumor tissue in the patient's prostate that is fluorescently illuminated by the near-infrared fluorescence imaging device.

[0027] In particular, green fluorescence is preferred for imaging the location of tumor tissue in the patient's prostate.

[0028] In particular, the fluorescence imaging (fluorescence brightening) is preferably green fluorescence imaging (green fluorescence brightening).

[0029] In particular, the near-infrared fluorescence imaging device performs fluorescence imaging of the tumor tissue of the patient's prostate based on the fluorescence intensity of the PAMA probe in the patient's urine. This means that when the fluorescence intensity of the PAMA probe in the patient's urine decreases 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 highlighted.

[0030] 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.

[0031] In particular, after the PAMA probe was injected into the patient using an injection device, the fluorescence intensity of the PAMA probe in the patient's urine was detected 2 hours after the injection was completed, starting from the end of the injection time; and the fluorescence intensity of the PAMA probe in the patient's urine was detected every 4 hours after the injection was completed, using a near-infrared fluorescence imaging device; and the amount of decrease in the fluorescence intensity of the PAMA probe in the patient's urine relative to the fluorescence intensity 2 hours after the injection was calculated.

[0032] In particular, the PSMA probe is a PSMA-targeted nuclide / fluorescent bimodal ligand of the structure shown in formula (2) labeled with a radionuclide.

[0033]

[0034] Equation (2)

[0035] In equation (2), n = 1, 2, 3, 4, preferably n = 3.

[0036] In particular, the radioactive nuclide 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 One of I, preferably 68 Ga.

[0037] The binding backbone of the bimodal PSMA probe used in the treatment device of the present invention, "O-Urea (ODAP-Urea)," has a PSMA-targeting binding ability comparable to that of the binding backbone Glu-Urea of ​​existing known bimodal PSMA-targeting probes derived from Glu-Urea inhibitors, and is more hydrophilic, which helps to balance the high hydrophobicity of cyanine dyes.

[0038] The dual-modal PSMA probe used in this treatment device 68 Ga-P1 to P4 uptake in the tumor region was significantly higher than in other non-target regions, especially 68 Ga-P3 exhibits good metabolic kinetics and can specifically concentrate in the tumor region in near-infrared I-zone optical imaging. The uptake in the tumor region reaches its peak at 2 hours, and the tumor region and surrounding tissues can be clearly distinguished after 4 hours. After 24 hours, the precise biodistribution data of major organs is consistent with the PET imaging results at earlier time points. It can be used for preoperative PET imaging and intraoperative near-infrared I-zone fluorescence navigation.

[0039] Animal experiments have shown that the dual-modal PSMA probe used in this therapeutic device is effective. 68 Ga-P1 to Ga-P4 have high safety profiles. In acute toxicity tests on normal mice, there was essentially no difference in body weight between 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. H&E staining results also showed no obvious pathological abnormalities in the major organs (heart, liver, spleen, lung, and kidney).

[0040] In particular, the amount of radionuclide used in the PSMA probe is (0.05-0.1) mCi / kg, preferably 0.1 mCi / kg.

[0041] In particular, the injection dose of the PSMA probe injected into the patient using an injection device is (0.004-0.04) mg / kg, preferably 0.04 mg / kg.

[0042] In particular, 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.

[0043] In particular, the fluorescence imaging module of the fluorescence laparoscope is the Huanocon fluorescence laparoscope system.

[0044] In particular, the near-infrared fluorescence imaging device integrates fluorescence imaging functionality with built-in "Firefly"® technology [Intuitive Surgical, Sunnyvale, CA, USA] and the Da Vinci robotic platform [IntuitiveSurgical, Sunnyvale, CA, USA].

[0045] In particular, the surgical robot used to remove the tumor tissue from the patient's prostate is a laparoscopic surgical robot, preferably the da Vinci Surgical System or the Condor Surgical System.

[0046] Compared with the prior art, the treatment device of the present invention has the following advantages:

[0047] 1. When using the treatment device of the present invention for radical prostatectomy, the postoperative margin positivity rate is significantly low, ≤18.8%;

[0048] 2. When using the treatment device of the present invention for radical prostatectomy, tumor tissue can be precisely removed under the guidance of fluorescence navigation during the operation, and the tumor tissue can be completely removed. If there is a positive surgical margin, the tumor tissue can be visualized in real time (i.e., fluorescently illuminated) by the near-infrared fluorescence imaging device of the treatment device of the present invention, and residual tumor tissue can be found. The tumor can be removed as completely and thoroughly as possible, reducing the positive margin rate, reducing the risk of postoperative biochemical recurrence, and improving the patient's prognosis.

[0049] 3. Since the neurovascular bundle is closely related to the prostate and urethra, the treatment device of this invention can help the surgeon determine whether there is residual tumor around the neurovascular bundle, improve the success rate of neurovascular bundle preservation, remove only the tumor tissue shown by fluorescence imaging, reduce the risk of various complications such as postoperative erectile dysfunction and urinary incontinence caused by neurovascular bundle damage, significantly reduce the impact on the patient's postoperative quality of life, and improve the postoperative quality of life of the patient.

[0050] 4. Using the treatment equipment of this invention, the PET / CT imaging device can detect the gross location of the prostate tumor in the patient, and the near-infrared fluorescence imaging device can perform fluorescence imaging of the tumor tissue during the operation to 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 facilitates the complete removal of the tumor tissue during the resection of the tumor tissue without damaging normal tissue or adjacent nerves and blood vessels, significantly reducing the risk of accidental injury to surrounding blood vessels and nerves during the operation and improving the safety of the operation.

[0051] 5. During the operation, the surgeon can operate the surgical robot of the treatment device of this invention with extremely high precision to perform fine operations and accurately remove tumors; and the surgical robot has high stability, which improves the success rate of the operation. Attached Figure Description

[0052] Figure 1 This is a schematic diagram of the structure of the treatment device of the present invention;

[0053] Figure 1A Fluorescence imaging sites of tumor tissue 68 PET imaging results of Ga-P3;

[0054] Figure 1B Fluorescence imaging sites of tumor tissue 68 CT imaging results of Ga-P3;

[0055] Figure 2 This is a fluorescence imaging image of tumor tissue during RP surgery using a near-infrared fluorescence imaging device. Detailed Implementation

[0056] The present invention will be further described in detail below with reference to embodiments, and the advantages and features of the present invention will become clearer with the description. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the present invention, but such modifications and substitutions all fall within the protection scope of the present invention. However, the implementation of the present invention is not limited thereto.

[0057] like Figure 1 The present invention provides a treatment device for reducing positive surgical margins after radical prostatectomy, comprising: an injection device, a PET / CT imaging device, a near-infrared fluorescence imaging device, and a surgical robot used in sequence, wherein:

[0058] The injection device is used to inject PSMA-targeted nuclide / fluorescent bimodal molecular probes (PSMA probes for short) into the patient's body, that is, to administer PSMA-targeted nuclide / fluorescent bimodal molecular probes to patients undergoing radical prostatectomy via intravenous injection;

[0059] The injection device of the present invention is an isotope injection device, that is, an injection device for injecting a patient with a radiolabeled tracer (i.e., a PSMA probe), comprising: a PSMA probe, a probe storage bottle, and a syringe, wherein the syringe is a disposable sterile syringe.

[0060] The prepared fluorescent nuclide dual-modal PSMA probe was placed in a sterile, pyrogen-free "negative pressure bottle," i.e., a probe storage bottle (Atomic High-Tech Co., Ltd., 10ml negative pressure bottle). The nurse then used a "disposable sterile syringe" (Shandong Weigao Group Medical Polymer Products Co., Ltd., 10ml) to draw it out and administer it to the patient intravenously.

[0061] The PSMA probe is: 68 The chelate of Ga with the ligand shown in structural formula (2) is a nucleic acid imaging reagent for prostate cancer, which is prepared according to the method of the authorized patent (a PSMA-targeted nuclide / fluorescent dual-modal ligand and molecular probe and its application, authorized announcement number CN114014843B).

[0062] The preparation steps of the PSMA probe of the present invention are as follows:

[0063] (a) First, synthesize the bimodal ligand (ODAP-PSMA targeted bimodal ligand); the structural formula of the ligand is shown in formula (2), where n=1, 2, 3, 4.

[0064] All reagents were purchased from reagent companies and were not purified. The coupling of amino acids was carried out according to the standard Fmoc solid-phase synthesis method.

[0065] 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-chlorotriphenylmethyl resin, DCM, DMF; (f) 20% piperidine in DMF solution, Fmoc-3-(2-naphthyl)-L-alanine, HBTU, HOBt and DIPEA in DMF solution; (g) 20% piperidine in DMF solution, Fmoc-(4-aminomethyl)benzoic acid, DMF solutions of HBTU, HOBt, and DIPEA; (h) 20% DMF solution of piperidine, DDE-Fmoc-L-lysine, HBTU, HOBt, and DIPEA; (i) 20% DMF solution of piperidine, DOTA, HBTU, HOBt, and DIPEA; (j) 2% DMF solution of hydrazine, Fmoc-L-aspartic acid-1-tert-butyl ester, HBTU, HOBt, and DIPEA; (k) 20% DMF solution of piperidine, LY-12, PyBOP, and DIPEA; (l) trifluoroacetic acid, water, and triisopropylsilane. All raw materials used were commercially available or prepared by conventional organic synthesis methods.

[0066] 100 mg of resin (0.03 mmol) was added to a 10 mL solid-phase synthesis tube, and 2 mL of dichloromethane (DCM) was added to swell the resin. This process was repeated three times, each time for 5 minutes. The mixture was then washed three times with N,N-dimethylformamide (DMF), each time for 5 minutes. The amino protecting group Fmoc was removed using a DMF solution (v / v) containing 20% ​​piperidine. Specifically, 2 mL of 20% piperidine DMF solution was reacted for 2 minutes, 10 minutes, and 10 minutes, followed by washing 3-5 times with 2 mL of DMF, each time for 2 minutes. Three times the stoichiometric amount of Fmoc amino acid, relative to the resin (0.03 mmol), was activated with 3.6 times the stoichiometric amount of HBTU or PyBOP in the presence of 7.2 times the stoichiometric amount of DIPEA and then added to the synthesis tube. The reaction was carried out under electromagnetic stirring for 1 hour. All deprotection, activation, and coupling steps, except for the deamino protecting group Dde step, were performed as described above. The amino protecting group Dde was removed using a DMF solution containing 2% hydrazine (v / v). Specifically, the reaction was performed with 2 mL of 2% hydrazine DMF solution for 2 minutes, 3 minutes, and 3 minutes respectively. Ligand dissociation from the resin and removal of tert-butyl ester were completed by stirring 5 mL of trifluoroacetic acid / triisopropylsilane / water (95:2.5:2.5, v / v / v) for 2 hours. The resin was then washed with 2 mL of trifluoroacetic acid, and all filtrates were collected. After removing trifluoroacetic acid under reduced pressure, the crude product was prepared by reversed-phase HPLC and lyophilized to obtain the target ligand.

[0067] (ii) Nuclide labeling

[0068] 68 Ga: Accurately weigh 1.0 mg of ligand into a sample tube, add 200 μL of DMSO (dimethyl sulfoxide) to dissolve it, and dilute the ligand concentration to 5 μg / μL. Pipette 6 μL of the ligand solution and 130 μL of NaOAc solution (1 mol / L) into a vial, and add 2 mL of freshly rinsed solution. 68 Ga 3+ An ionic solution (0.05 mol / L hydrochloric acid solution with a radioactivity of 10⁻¹⁷ mCi) was prepared, shaken well, sealed, and reacted at 90°C for 10 minutes. The reaction solution was then cooled to room temperature.

[0069] The treatment device of this invention uses a PSMA probe prepared according to the invention patent with authorization announcement number CN114014843B. 68 The concentration ratio of Ga was (0.01-0.1) / 0.1 mCi / kg; the injection dose of the PSMA probe was (0.004-0.040) mg / kg.

[0070]

[0071] Equation (2)

[0072] In equation (1), n ​​= 1, 2, 3, 4.

[0073] In a specific embodiment, the PSMA probe ligand n=3, and the radioactive element is... 68 Ga, abbreviated as Ga 68 Ga-P3.

[0074] PET / CT imaging equipment is a detection device used to display the gross location of prostate tumors in patients who have been injected with PSMA probes. Specifically, it is used to image the head and trunk of patients who have been injected with PSMA probes and are scheduled for radical prostatectomy to determine the gross location of the prostate tumors.

[0075] A PET / CT imaging system includes: a PET detector, a CT scanner, a PET / CT fusion system, a data acquisition system, an image reconstruction and processing computer, a control panel and operating system, a patient bed, an isotope injection device, and an auxiliary support system; among which:

[0076] PET detectors, also known as PET modules, are used to detect positrons (or gamma rays) emitted from radioactive isotopes injected into the human body.

[0077] A CT scanner is used to perform X-ray scans on a patient's body to obtain high-resolution images of cross-sections;

[0078] PET and CT fusion systems are used to fuse image data from PET detectors and CT scanners to generate a comprehensive image, allowing doctors to view the overlap information of the two scan images simultaneously.

[0079] The data acquisition system is used to acquire signals from PET detectors and CT scanners and convert them into digital data; the system is responsible for signal amplification, sampling and transmission to ensure the accuracy of image quality.

[0080] The image reconstruction and processing computer is used to reconstruct and process images from data acquired by the data acquisition system; the processing computer converts raw data from PET and CT into three-dimensional images and performs data fusion to generate comprehensive images of the patient so that doctors can make a diagnosis.

[0081] The control panel and operating system are used by the operator to control various settings, scanning processes, and data storage of the PET / CT equipment; they typically include a touchscreen interface or computer interface for operating and monitoring the scanning process.

[0082] A patient bed, also known as a scanning bed, is used for patient positioning and immobilization, keeping the patient in the correct position during scanning. The bed is usually adjustable to ensure that the patient can be accurately positioned in the scanning area.

[0083] Auxiliary and support systems include power management, cooling systems, emergency shutdown systems, and safety monitoring systems to ensure stable operation of the equipment and provide safety for patients and operators. Detectors and other electronic components in PET / CT equipment need to be kept at appropriate temperatures, and cooling systems are used to maintain stable operation of the equipment.

[0084] PET / CT Examination Procedure: The patient lies supine on the PET / CT patient bed, breathing calmly. The head and trunk acquisition conditions are as follows: the scan range extends from the top of the head to the upper third of the thigh. After injecting the tracer (PSMA probe), the patient rests for approximately 30-120 minutes to allow the tracer to distribute throughout the body.

[0085] During injection 68 Two hours after Ga-P3 administration, PET / CT imaging is performed. The PET detector begins to capture the spatial distribution of positrons emitted by the radioactive tracer throughout the patient's body and generates images. The CT scanner provides high-resolution images of the anatomical structures. The PET / CT fusion system combines the PET and CT image data to form a PET / CT image, which fully displays the primary prostate cancer lesion and the localization of pelvic lymph nodes. It also obtains the gross location of the prostate tumor in patients injected with PSMA probes for subsequent diagnosis. Furthermore, the surgeon can use the PET / CT images to roughly locate the lesion and formulate a specific plan for tumor resection surgery.

[0086] Normal injection 68 RARP was performed 24±6 hours after Ga-P3 was absorbed.

[0087] A near-infrared fluorescence imaging device is used to display the fluorescence levels of tumor tissue and normal tissue in the prostate of a patient injected with a PSMA probe; and to perform fluorescence imaging of the tumor tissue of the patient's prostate based on the fluorescence intensity of the PSMA probe in the urine after the injection of the PSMA probe, i.e., to highlight the tumor tissue of the patient's prostate with fluorescence. In a specific embodiment of the present invention, green fluorescence imaging of prostate tumor tissue is used as an example for illustration.

[0088] The near-infrared fluorescence imaging device includes: a near-infrared light source, a probe, and a fluorescence imaging display, wherein:

[0089] Near-infrared light source: emits near-infrared light (such as wavelengths of 750-800nm) to excite fluorescent dyes;

[0090] Probe: Used to irradiate the surgical area with near-infrared light and capture the fluorescence signal emitted from the target tissue;

[0091] 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.).

[0092] The specific functions of the near-infrared fluorescence imaging device are as follows:

[0093] 1) Used to detect the fluorescence intensity or concentration of PSMA probe in urine. After injection of PSMA-targeted nuclide / fluorescent dual-modal probe (hereinafter referred to as PSMA probe), the fluorescence intensity of PSMA probe in the patient's urine is detected every 4 hours using a near-infrared fluorescence imaging device; and the fluorescence intensity of PSMA probe in the patient's urine is detected 2 hours after injection.

[0094] 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 decreases by ≥90% compared to the fluorescence intensity 2 hours after injection, a radical resection of the tumor tissue of the patient's prostate is performed under the fluorescence guidance of a near-infrared fluorescence imaging device.

[0095] 3) Near-infrared fluorescence imaging device is used to perform fluorescence imaging on the patient's prostate tumor tissue. The patient's prostate tumor tissue exhibits specific fluorescence under the near-infrared fluorescence imaging device (green fluorescence is used as an example in this embodiment), which makes the tumor tissue distinguishable from the normal tissue of the prostate. This facilitates the complete removal of the tumor tissue during the tumor removal process without damaging the normal tissue or adjacent nerves and blood vessels. It significantly reduces the risk of accidental injury to surrounding blood vessels and nerves during surgery and reduces the positive margin rate.

[0096] The near-infrared fluorescence imaging device can be either the Firefly imaging system (i.e., video imaging system) of the da Vinci surgical robot or a near-infrared fluorescence laparoscope.

[0097] Near-infrared fluorescence laparoscopes have the functions of conventional laparoscopes 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), they can capture fluorescence signals and generate images. They can also display conventional laparoscope images and fluorescence images at the same time, and display the fluorescence distribution of the target area in real time.

[0098] 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 Huanocon fluorescence laparoscopic system.

[0099] Laparoscopy includes conventional laparoscopes, fluorescence laparoscopes, 3D laparoscopes, etc.

[0100] The fluorescence laparoscopic system in this invention is a near-infrared fluorescence laparoscopy.

[0101] The da Vinci Surgical System is equipped with a fluorescence imaging system called "Firefly".

[0102] Condor and da Vinci are two different brands of robotic surgical systems.

[0103] Near-infrared fluorescence imaging system operating procedure:

[0104] 1. The PSMA probe was injected into the patient intravenously using an isotope injection device. 68 Ga-P3);

[0105] 2. Near-infrared fluorescence imaging device was used to detect the fluorescence intensity of PSMA probe in the urine of patients 2 hours after injection and to detect the fluorescence intensity of PSMA probe in the urine of patients every 4 hours after injection. Among them, when the fluorescence intensity of PSMA probe in the urine of patients decreased by ≥90% compared with the fluorescence intensity 2 hours after injection, RARP surgery was performed on the patients.

[0106] 3. During the operation, a near-infrared fluorescence imaging device is used to perform fluorescence imaging on the tumor tissue of the patient's prostate (i.e., fluorescence brightening / displaying of tumor tissue; in this embodiment of the invention, green fluorescence is used to brighten the tumor tissue); and to accurately display the location of the tumor tissue and clearly show the boundary and limit between the tumor tissue and normal tissue.

[0107] During the surgery, the near-infrared light source of the near-infrared fluorescence imaging device emits near-infrared light of a specific wavelength, which irradiates the body area, activates the PSMA probe injected into the body, and fluorescently visualizes the tumor tissue.

[0108] The activated fluorescent dye in the PSMA probe emits a fluorescent signal at a specific wavelength, which is captured by the fluorescence imaging module of a near-infrared fluorescence imaging device via the laparoscope probe. The imaging system of a near-infrared fluorescence laparoscopy simultaneously displays ordinary visible light images and fluorescence images, typically employing image fusion technology to combine the two images for display. This allows surgeons to distinguish between normal tissue and the target area containing the fluorescent dye (prostate cancer tissue).

[0109] 4. During the surgery, the surgeon performs precise surgical operations based on the information displayed by the near-infrared fluorescence imaging device (such as the Firefly system of the da Vinci surgical robot or the fluorescence laparoscopic system), so as to completely remove the prostate and prostate tumor while minimizing damage to the surrounding structures.

[0110] A surgical robot is used to remove the tumor tissue of a patient's prostate based on the gross location of the prostate tumor shown by a PET / CT imaging device and the precise location of the tumor tissue in the patient's prostate tissue as shown by near-infrared fluorescence imaging device (i.e., fluorescence brightening, such as green fluorescence brightening). This robot is used to perform standardized transperitoneal RARP (robot-assisted radical prostatectomy). Based on the extent of the fluorescence-positive area, the extent and size of the prostate tumor tissue are determined, and the prostate and the tumor tissue in the fluorescence-positive area are completely removed.

[0111] The fluorescently positive area is the tissue area for fluorescence imaging. In this embodiment, green fluorescence imaging is used for illustration. That is, the green fluorescence display area is the fluorescently positive area.

[0112] The surgical robot is an endoscopic surgical control system. The surgical robot device selected is a laparoscopic surgical robot, such as the da Vinci Surgical System (intuitive surgical instruments and technologies, Sunnyvale, CA, USA) or the Condor Surgical System (Suzhou Condor Robotics Co., Ltd., Suzhou, China).

[0113] Laparoscopic surgical robots include: a robot control console, a surgical robotic arm system, and a video imaging system.

[0114] Surgical robots typically have multiple robotic arms (usually 3-4), each capable of precisely manipulating different tools, such as cameras and various surgical instruments. The robotic arms move with remarkable dexterity, mimicking the movements of a surgeon's hand and even surpassing the dexterity and stability of the hand, thus avoiding hand tremors common in traditional surgery.

[0115] The surgeon operates from a control console, using the console's controllers to perform surgery on the robot. The console provides a 3D high-definition view and allows for precise control of the robot's arms and tools via hand controllers and foot pedals. Through highly precise hand movements, the surgeon can perform delicate procedures.

[0116] The da Vinci surgical robot used in this specific embodiment of the invention is also called an "endoscopic surgical 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 console, observes the surgical field through a stereoscopic eyepiece, and remotely controls the bedside robotic arm and camera to complete the surgery via a controller. The controller allows for precise synchronization between the surgical instruments and the surgeon's hands.

[0117] Robot usage process:

[0118] At the start of the surgery, the surgeon obtains a 3D high-definition view of the surgical area on a monitor at the robotic console, providing a clearer and magnified view than traditional laparoscopy. The surgeon precisely controls each arm of the robot using joysticks and foot pedals on the console, enabling it to perform specific operations. The arms can perform complex movements like human hands, such as rotation, grasping, and cutting. At the start of the surgery, one arm may be responsible for operating the laparoscopic camera, while the other arm is used to manipulate surgical instruments. The robotic arms' dexterity far surpasses traditional surgical methods, allowing for easier access to hard-to-reach cavities or anatomical areas.

[0119] The robotic operation of the treatment device of the present invention has the following advantages and benefits:

[0120] Precision manipulation: With the assistance of robotic systems, surgeons can perform operations with extremely high precision. For example, when removing a tumor, a robot can help doctors precisely remove the tumor while minimizing damage to surrounding healthy tissue.

[0121] High stability: The robotic system can reduce the slight vibration of the doctor's hands, ensuring the stability of the surgical procedure, especially when performing delicate operations.

[0122] The working principle of the treatment device for reducing positive surgical margins after radical prostatectomy of the present invention is as follows:

[0123] 1. PSMA probes were prepared according to the method of the authorized patent (A PSMA-targeted nuclide / fluorescent bimodal ligand and molecular probe and its application, authorized publication number CN114014843B). In the specific embodiments of this invention, the PSMA probes were selected based on quality control. 68 Ga-P3 (0.05-0.1 mCi / kg).

[0124] 2. Based on the patient's weight (kg) before radical prostatectomy, and according to the injection dose of PSMA probe (0.004-0.020 mg / kg), accurately draw the required amount of PSMA probe using a disposable sterile syringe. 68 Ga-P3 (0.05-0.1 mCi / kg) is administered intravenously to the patient. For example, if the patient weighs 70 kg, a PSMA probe is injected. 68 The amount of Ga-P3 is 70 × 0.01 = 0.7 mg.

[0125] 3. For injection 68At 0.5 hours, 1 hour, and 2 hours after taking Ga-P3 (0.05-0.1 mCi / kg), PET / CT imaging was performed on the patient's head and trunk, with the scanning range extending from the top of the head to the upper third of the thigh. The patient was placed supine on the PET / CT examination table, breathing calmly. Head and trunk acquisition conditions were the same as above. Data were reconstructed using OSEM to obtain coronal, sagittal, and transverse PET / CT fused images, clearly showing the primary prostate cancer lesion and pelvic lymph node location. PET / CT parameters were acquired using MedEx MEMRS V8.0 software.

[0126] injection 68 Two hours after the Ga-P3 probe is applied, PET / CT imaging shows clear results, allowing for the localization of the prostate cancer lesion using radionuclide localization. This enables the approximate location of the patient's prostate tumor tissue to be determined, preserved, and recorded. Figure 1A , 1B .

[0127] 4. After injection of the PSMA probe, timing was started from the end of the injection, and the fluorescence intensity of the PSMA probe in the patient's urine was measured using a near-infrared fluorescence imaging device 2 hours after injection; and

[0128] Timing begins at the end of the injection. Using a near-infrared fluorescence imaging device, the fluorescence intensity of the PSMA probe in the patient's urine is detected every 4 hours (usually 2-8 hours) until the fluorescence intensity of the PSMA probe in the urine decreases by more than 90% relative to the fluorescence intensity of the PSMA probe in the patient's urine 2 hours after injection, at which point radical prostatectomy is prepared.

[0129] The fluorescence intensity decay of PSMA probes in patients' urine is detected by near-infrared fluorescence imaging device to avoid residual PSMA probes in patients' urine contaminating the surgical area during RARP.

[0130] 5. A standardized transperitoneal approach to RARP is performed using a surgical robot, typically during injection. 68 The surgical robot performs RARP at 24±6 hours after the Ga-P3 test (the metabolic rate of the PSMA probe varies depending on the patient's constitution).

[0131] The surgical robot device used is the da Vinci Si / Xi surgical system (Intuitive Surgical, Sunnyvale, CA, USA).

[0132] Following a standardized fluorescence-guided surgical procedure, the Firefly fluorescence system (near-infrared fluorescence imaging device) of the da Vinci Si / Xi surgical system of the surgical robot was used to observe the region of interest (i.e., the various surfaces of the prostate and the surgical wound after resection) at a distance of approximately 4 cm, and the surgical process was recorded on video.

[0133] The specific procedure for fluorescence-guided surgery is as follows:

[0134] First, the prostate and pelvic lymph nodes are examined in fluorescence mode; near-infrared fluorescence imaging device displays the fluorescence imaging results of prostate tumor tissue, such as... Figure 2 ;

[0135] The surgical robot uses a near-infrared fluorescence imaging device to perform fluorescence imaging during radical prostatectomy on the green fluorescent bright area of ​​the patient's prostate. Figure 2 As shown. Figure 2 The area marked by the dashed line represents the precise location of the tumor tissue as visualized by the near-infrared fluorescence imaging device.

[0136] Subsequently, RP (radical prostatectomy) was performed under fluorescence navigation. Before opening the bladder neck, the bladder was flushed via the urethra to further reduce the amount of probe residue in the bladder and avoid PSMA probes in the urine. 68 Ga-P3) residual contamination area; after opening the bladder neck, use fluorescence mode to observe the prostate and bladder neck;

[0137] Next, under fluorescence navigation, the prostate and prostate tumor were completely removed. After the resection, the condition of each resection margin was observed, including whether the fluorescently positive areas at each margin still showed fluorescence, and whether there was any residual fluorescence in the surgical area. After confirming that there was no residual fluorescence, the surgery was terminated. The entire surgical process was recorded on video.

[0138] Finally, the fluorescently positive areas of the prostate were marked with biological dyes after the operation to identify the fluorescently positive areas during histopathological analysis.

[0139] The decision to perform e-PLND (extended pelvic lymph node dissection) is made based on the patient's risk level, preoperative imaging examinations, and the patient's own wishes. For patients requiring e-PLND, the surgeon uses a surgical robot to perform a standardized e-PLND procedure, using a near-infrared fluorescence imaging device to observe whether each lymph node region has fluorescence imaging, removing the fluorescently positive lymph nodes and sending them separately for histopathological analysis.

[0140] 6. Perform histopathological analysis on the tissue removed during radical prostatectomy.

[0141] Prostate and lymph node tissue sections were paraffin-embedded to obtain thin-layer tissue sections. Three consecutive sections were prepared for tumor-positive or fluorescent prostate and lymph node tissue blocks: one section was used for H&E staining for tumor assessment, which serves as the gold standard for tumor detection; one section was used for PSMA immunohistochemical staining to evaluate PSMA overexpression; and one section was used for PSMA immunofluorescence staining. The consistency of H&E staining, PSMA immunohistochemical staining, and immunofluorescence staining was observed.

[0142] A prospective single-arm clinical study using the treatment device of this invention in humans with PSMA probes. 68 Ga-P3 was used in preoperative imaging and intraoperative navigation for prostate cancer. This study included 16 patients with intermediate- to high-risk localized or locally advanced prostate cancer, who underwent intravenous injection of different doses of Ga-P3. 68 Ga-P3 (6 cases 0.004 mg / kg, 5 cases 0.010 mg / kg, 5 cases 0.020 mg / kg) was administered via PET / CT imaging at 0.5 h, 1 h, and 2 h post-injection for preoperative staging of prostate cancer; [further details regarding injection are needed for accurate translation.] 68 After Ga-P3 treatment, once the fluorescence intensity in the patient's urine decreased by ≥90% compared to the fluorescence intensity in the patient's urine 2 hours after injection, RARP+e-PLND under fluorescence navigation was performed, and the fluorescently positive areas were marked for histopathological analysis.

[0143] None of the patients showed any symptoms related to the injection. 68 Ga-P3 or adverse reactions related to intraoperative fluorescence navigation. Histopathological analysis indicated that all fluorescently positive areas were tumor remnants or tumors near the surgical margin. The PSM (positive surgical margin) rate of RARP under fluorescence navigation was 18.8%, significantly lower than the current positive surgical margin rate after radical prostatectomy.

[0144] Therefore, the safety and effectiveness of RARP surgery are significantly improved by using the treatment device of the present invention for preoperative PET imaging and intraoperative fluorescence navigation in prostate cancer surgery.

[0145] The above embodiments of the present invention are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope thereof, but all such modifications and substitutions fall within the protection scope of the present invention.

Claims

1. A treatment device for reducing positive surgical margins after radical prostatectomy, characterized in that, include: An injection device for injecting PSMA-targeted nuclide / fluorescent dual-modal molecular probes, i.e., PSMA probes, into patients. A PET / CT imaging device used to display the location of prostate tumors in patients who have been injected with PSMA probes; 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 used to completely remove the patient's prostate and tumor tissue based on the location of the patient's prostate tumor as shown by a PET / CT imaging device and the location of the tissue as shown by a positive intraoperative near-infrared fluorescence imaging device; The near-infrared fluorescence imaging device performs fluorescence imaging of the tumor tissue of the patient's prostate based on the fluorescence intensity of the PAMA probe in the patient's urine. This means that when the fluorescence intensity of the PAMA probe in the patient's urine decreases 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 highlighted. The PSMA probe is a PSMA-targeted nuclide / fluorescent bimodal ligand labeled with radionuclide as shown in formula (2). Equation (2) In equation (2), n = 1, 2, 3, 4.

2. The treatment device according to claim 1, characterized in that, In equation (2), n=3.

3. The treatment 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 PAMA probe fluorescence intensity in the patient's urine.

4. The treatment device according to claim 3, characterized in that, The radioactive nuclide 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 One of them is I.

5. The treatment device according to claim 4, characterized in that, The radioactive nuclide is 68 Ga.

6. The treatment device according to claim 5, characterized in that, The amount of radionuclide used in the PSMA probe is (0.05-0.1) mCi / kg.

7. The treatment device according to claim 6, characterized in that, The amount of radionuclide used in the PSMA probe is 0.1 mCi / kg.

8. The treatment device according to claim 1 or 2, characterized in that, The injection dose of the PSMA probe administered to the patient using an injection device is (0.004-0.04) mg / kg.

9. The treatment device according to claim 8, characterized in that, The injection dose of the PSMA probe administered to the patient using an injection device is 0.04 mg / kg.

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

11. The treatment device according to claim 1 or 2, characterized in that, For the surgical removal of tumor tissue from the patient's prostate, a laparoscopic surgical robot was chosen.

12. The treatment device according to claim 11, characterized in that, The surgical robot used to remove the tumor tissue from the patient's prostate is either the da Vinci Surgical Robot or the Condor Surgical Robot.

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