Photodynamic therapy system for treating bladder cancer

Abstract

The invention relates to a photodynamic therapy system for treating bladder cancer, and belongs to the technical field of photodynamic therapy. The system comprises a treatment catheter assembly used for performing laser energy delivery and biosensing signal acquisition on a bladder lesion area; the central control unit is used for data processing and control signal generation, and the central control unit can obtain tissue oxygen partial pressure and singlet oxygen concentration according to the biosensing signals collected by the treatment catheter assembly and generate control signals used for regulating and controlling laser energy delivery operation of the treatment catheter assembly according to the tissue oxygen partial pressure and the singlet oxygen concentration; the treatment catheter assembly can perform laser energy delivery operation on tumor tissue in a bladder lesion area in an intermittent mode, the interval time length and applied illumination parameters are changed based on the real-time concentration change condition of singlet oxygen, and the illumination parameters comprise light intensity and wavelength.

Description

Technical Field

[0001] The present invention relates to the technical field of photodynamic therapy, and in particular to a photodynamic therapy system for treating bladder cancer. Background Art

[0002] Photodynamic therapy (PDT) is a treatment method that uses photodynamic reactions to selectively kill tumor cells. This method typically involves injecting a photosensitizer, which is absorbed by the tumor, into the patient's bladder. Light of a specific wavelength and band is then directed through an optical fiber, which is then used to generate laser-like "irradiation energy" to irradiate the entire bladder. The intensity and duration of the light irradiation are crucial for generating therapeutic singlet oxygen at the lesion site.

[0003] Weiying Hou, Ye Yuan, Zezhou Sun, Shuxu Guo, Haowen Dong, Changfeng Wu et al. published an article titled "Ratiometric Fluorescent Detection of Intracellular Singlet Oxygen by Semiconducting Polymer Dots" in the American Chemical Society on November 22, 2018. As a methodological study, the article developed a ratiometric fluorescent probe based on semiconductor polymer dots (Pdots) for singlet oxygen ( 1 The study used a singlet oxygen fluorescence probe SOSG doped polyfluorene Pdots system to achieve blue fluorescence (constant reference signal) and green fluorescence (with 1 O2 production is enhanced) ratio response. The experiment is generated in situ in cells by combining photosensitizers with light. 1 O2, using spectral measurement (excitation wavelength 375nm) and confocal imaging technology to monitor the intracellular 1 The results showed that SOSG-doped Pdots exhibited green fluorescence intensity and 1 The linear response relationship between the blue and green fluorescence intensity was observed, and the blue / green fluorescence intensity ratio changed significantly, confirming that the probe has a strong affinity for intracellular O2. 1 O2 detection is highly sensitive and reliable.

[0004] Although studies have confirmed that singlet oxygen ( 1Although O2) can be detected sensitively and reliably, it is still difficult to use it directly in clinical photodynamic therapy, especially photodynamic therapy using traditional intermittent control strategy.

[0005] The main shortcoming of traditional intermittent control strategies in photodynamic therapy is their lack of adaptability to biophysical response mechanisms. The fixed intermittent cycle design does not fully consider the spatial differences in tissue oxygen diffusion rate, which is mainly due to the heterogeneous characteristics of the tumor microenvironment itself: the uneven oxygen supply caused by the abnormal blood vessel distribution inside the tumor leads to an order of magnitude difference of more than 10 times in the oxygen diffusion rate of different regions. When a unified intermittent cycle is adopted, the rapid oxygen recovery in areas with high vascular density and the slow oxygen recovery in areas with low vascular density produce a contradictory phenomenon. Specifically, the high-density area leads to a decrease in the activation efficiency of the photosensitizer due to the long intermittent period, while the low-density area causes the accumulation of phototoxic substances due to insufficient oxygen supplementation. Continuing to use a fixed intermittent strategy may cause thermal damage to normal tissues due to excessive energy concentration in oxygen-rich areas, while the hypoxic area forms a treatment blank area due to insufficient energy delivery.

[0006] The current control strategy is also insufficient in that the partial pressure of oxygen in tissues (PO2) and singlet oxygen ( 1 The dynamic coupling mechanism of the O2 concentration is missing. During the photodynamic reaction, the concentration of singlet oxygen generated by the photosensitizer is not only related to the initial oxygen partial pressure, but also dynamically regulated by the photobleaching effect and the oxygen consumption rate. The existing methods fail to construct a dynamic correlation equation between the two, resulting in the decrease of oxygen reserves in the later stage of treatment. 1 O2 generation efficiency exhibits a nonlinear downward trend. If this issue is not effectively addressed, photosensitizer activation efficiency may drop sharply in the middle and late stages of treatment, forcing clinical practice to resort to compensatory measures such as increasing light intensity. This practice accelerates oxygen depletion, creating a vicious cycle of decreased therapeutic efficacy and increased side effects, significantly increasing the risk of bladder mucosal fibrosis.

[0007] Another limitation of existing strategies is that a quantitative relationship model between oxygen recovery time and tumor vascular density has not been established. As the core parameter that determines the oxygen diffusion rate, vascular density directly affects the accuracy of calculating the optimal interval. Traditional methods rely on empirical formulas to estimate recovery time, but ignore the structural specificity of tumor neovascularization - these blood vessels have abnormal permeability due to incomplete development of the basement membrane, forming an interstitial high-pressure environment that hinders the diffusion of oxygen molecules. Long-term neglect of this correlation will lead to the treatment system misassessing the oxygen recovery capacity of areas with low vascular density, especially in the treatment of angiogenesis-inhibiting tumors, which may cause large-scale hypoxic necrosis and activate the HIF-1α signaling pathway to promote tumor invasive development.

[0008] Therefore, there is an urgent need in this field for a solution based on laser regulation and oxygen compensation optimization to dynamically adjust laser pulses and intermittent periods, thereby optimizing oxygen dynamics in bladder tumor treatment and improving the effect of photodynamic therapy.

[0009] In addition, on the one hand, there are differences in understanding among those skilled in the art; on the other hand, the applicant studied a large number of documents and patents when making the present invention, but due to space limitations, not all details and contents are listed in detail. However, this does not mean that the present invention does not have the characteristics of these prior arts. On the contrary, the present invention already has all the characteristics of the prior art, and the applicant reserves the right to add relevant prior art to the background technology. Summary of the Invention

[0010] In view of the shortcomings of the existing technology, the present invention aims to provide a photodynamic therapy system for treating bladder cancer, which optimizes the recovery of tissue oxygen partial pressure (PO2) during intermittent laser pulses, and improves singlet oxygen ( 1 The generation efficiency of O2) can be improved to optimize the oxygen dynamics in bladder tumor treatment, thereby solving at least part of the above-mentioned technical problems.

[0011] The present invention discloses a photodynamic therapy system for treating bladder cancer, comprising: a treatment catheter assembly for delivering laser energy and collecting biosensor signals to a bladder lesion region; and a central control unit for processing data and generating control signals. The central control unit can obtain tissue oxygen partial pressure and singlet oxygen concentration based on the biosensor signals collected by the treatment catheter assembly, and use these to generate control signals for regulating the laser energy delivery operation of the treatment catheter assembly, enabling the treatment catheter assembly to intermittently deliver laser energy to tumor tissue in the bladder lesion region. The interval length and applied illumination parameters, including light intensity and wavelength, vary based on real-time changes in singlet oxygen concentration.

[0012] The treatment catheter assembly includes an irradiation module for irradiating the bladder lesion area, emitting light that includes both therapeutic and excitation light; a first monitoring module for real-time measurement of oxygen partial pressure distribution data within the tumor tissue in the bladder lesion area; and a second monitoring module for capturing and quantifying the spatial distribution of singlet oxygen during photodynamic therapy. The biosensor signals collected by the first and second monitoring modules are transmitted to a central control unit for data processing to determine tissue oxygen partial pressure and singlet oxygen concentration, thereby generating control signals for regulating the irradiation module's interval length and applied illumination parameters.

[0013] The treatment catheter assembly adopts a multi-layer composite structure design, and its multiple independent cavities include drug infusion channels, so that when the photodynamic therapy system is activated, the treatment catheter assembly can be introduced into the patient's bladder and positioned at the bladder lesion area, and then the bladder lesion area is infused with a drug composition containing a photosensitizer through the drug infusion channel.

[0014] During the initialization phase, the irradiation module can output a detection beam according to the preset parameters generated by the central control unit, so that the central control unit can receive the oxygen partial pressure data of the tumor tissue in the bladder lesion area obtained by the first monitoring module, and then calculate the oxygen recovery time constant.

[0015] After entering the treatment stage, the central control unit can generate a pulse width modulation signal based on the built-in adaptive intermittent control algorithm to drive the irradiation module to perform adaptive intermittent irradiation on the bladder lesion area. When the irradiation module irradiates the bladder lesion area, the second monitoring module can capture the phosphorescence signal and / or fluorescence signal, and then send it to the central control unit for data processing to obtain the singlet oxygen concentration.

[0016] The central control unit performs a three-dimensional treatment response surface reconstruction every preset time to enhance the oxygen Updated treatment effectiveness index for each region This allows the central control unit to adjust the interval length and / or applied light parameters based on changes in the treatment efficacy index.

[0017] The central control unit can calculate the oxygen enhancement factor based on real-time and therapeutic efficacy index Perform one or more of the following adjustments:

[0018] When the therapeutic efficacy index Decrease, increase the laser intensity in that area proportionally to compensate for the loss of therapeutic effect;

[0019] For areas where the oxygen enhancement factor is below a preset threshold, the proportion of therapeutic light is increased and the proportion of excitation light is reduced;

[0020] Based on the reconstructed three-dimensional treatment response surface, the light spot residence time of tumor tissue with relatively higher treatment efficacy index in the bladder lesion area is extended, and the light spot residence time of tumor tissue with relatively lower treatment efficacy index is shortened.

[0021] When making adjustments, the central control unit can establish a dynamic adjustment mechanism for the safety threshold value that depends on the oxygen partial pressure based on a preset set of safety constraint equations.

[0022] The dynamic intermittent control strategy proposed in the present invention not only improves the efficacy of direct treatment, but also synchronously triggers the tumor microenvironment immune regulatory network. Its mechanism is manifested as follows: through the gradient oxygen partial pressure regulation during the intermittent period, the generation of an immunosuppressive microenvironment caused by sustained hypoxia is suppressed; at the same time, the cyclic characteristics of photodynamic damage are utilized so that the generated tumor-associated antigen fragments are preferentially recognized and captured by antigen-presenting cells during the oxygen concentration recovery phase. This alternating damage-repair mode can induce the gradient release of damage-associated molecular patterns (DAMPs), enhance the maturation and directional migration ability of dendritic cells, and ultimately drive CD8+ T cell-specific anti-tumor immune responses. This immune synergistic effect forms a functional complement to the single cytotoxic effect of conventional PDT, jointly constructing a dual protection system to inhibit tumor recurrence.

[0023] In another aspect, the present invention relates to a photodynamic therapy system for treating bladder cancer, capable of enhancing the specificity of photodynamic therapy. The system comprises: an irradiation module equipped with multiple blue light sources; a drug delivery module for injecting a pharmaceutical composition containing a photosensitizer into the patient's bladder; and a central control unit. The central control unit is communicatively connected to the irradiation module and the drug delivery module.

[0024] The central control unit can control the drug administration module to inject a pharmaceutical composition containing a photosensitizer into the patient's bladder. The central control unit is configured to allow a certain period of time to allow the photosensitizer to accumulate in the bladder cancer cells. After the drug administration module injects the pharmaceutical composition containing the photosensitizer into the patient's bladder, the central control unit can control the irradiation module to provide the patient with light in a wavelength range of 400 to 700 nanometers after a preset accumulation time (the time it takes for the photosensitizer to accumulate in the bladder cancer cells), and irradiate blue light into the patient's bladder at a light intensity of 1.5 to 12.5 milliwatts per square centimeter. Under the control of the central control unit, the irradiation time of the irradiation module is selected to be applied in an intermittent manner, wherein the irradiation time applied intermittently by the irradiation module refers to the irradiation module applying blue light for a preset treatment duration at a preset light intensity every several minutes.

[0025] The present invention also relates to a photodynamic therapy method with enhanced photodynamic therapy specificity or intermittent photodynamic therapy method for treating bladder cancer, the method comprising the following steps: (a) injecting a photosensitizer into the patient's bladder; (b) allowing a certain period of time to allow the photosensitizer to accumulate in the bladder cancer cells; (c) exposing the tumor tissue to blue light for a predetermined period of time; wherein the selected blue light is sufficient to activate the photosensitizer to generate a sufficient amount of reactive oxygen species to kill the bladder cancer cells without causing significant damage to surrounding healthy tissues.

[0026] Preferably, the light intensity and / or exposure time are selected to be sufficient to activate the photosensitizer. The blue light of the predetermined light intensity and / or exposure time acts on the pharmaceutical composition containing the photosensitizer to generate a sufficient amount of reactive oxygen species to kill the bladder cancer cells without causing significant damage to surrounding healthy tissue.

[0027] Preferably, the wavelength of the light is in the range of 400 to 500 nanometers, more preferably, the wavelength of the light is in the range of 450 to 500 nanometers.

[0028] Preferably, the present invention can be applied to the photodynamic therapy of superficial bladder cancer, non-muscle invasive bladder cancer or muscle invasive bladder cancer.

[0029] The photodynamic therapy method used by Xibofen (hematoporphyrin injection) which is currently on the market is: using a 630-nanometer wavelength laser to irradiate tumor tissue. Although the full scope and exact nature of the biological effects of blue light on biological tissues of Xibofen are still unclear, the technical solution involved in the present invention is that those skilled in the art unexpectedly discovered that during the photodynamic therapy of superficial multiple bladder cancer, Xibofen excited by blue light can better promote the reaction speed and efficiency of active oxygen in the tissue. At the same time, because the penetration of blue light is weaker than that of red light, and blue light is a "cold light source", in multiple and long-term irradiation treatments, blue light can reduce the damage and temperature effects on normal tissues (especially deep tissue areas with rich blood flow, which can reduce the effects of Xibofen on them) compared to red light.

[0030] At the same time, considering the interaction between the three essential elements for the therapeutic effect of photodynamic therapy, namely light, photosensitizer, and singlet oxygen, the present invention further sets an intermittent lighting mode.

[0031] This mode is designed to optimize treatment efficacy by controlling the duration and frequency of illumination, creating a time window for oxygen recovery and the involvement of singlet oxygen in cell apoptosis. This allows the illumination module to more precisely activate the photosensitizer and improve the efficiency of singlet oxygen generation. Furthermore, intermittent illumination can reduce thermal damage and phototoxic reactions to tissues, improving treatment safety and patient comfort.

[0032] The pharmaceutical composition containing a photosensitizer may comprise one or more pharmaceutically acceptable carriers or excipients.

[0033] The illumination intensity of the irradiation module is controlled by adjusting the power of the irradiation module and / or the distance between the patient's bladder and the irradiation module by the central control unit, wherein the distance between the patient's bladder and the irradiation module is calibrated according to the degree of bladder filling caused by the injection of the pharmaceutical composition containing the photosensitizer, and preferably, the degree of bladder filling is also adjusted according to the injection duration of the pharmaceutical composition.

[0034] The intensity of light used to excite the photosensitizer is affected by the state of bladder filling. Given the dynamic nature of the body's metabolism, the patient's bladder filling volume is not constant during treatment, resulting in changes in bladder filling level. After emptying the bladder, the bladder's recovery state will vary at different time points due to the influence of diseased tissue on bladder elasticity recovery. Therefore, the distance between the irradiation module and the inner wall of the bladder may vary. Because the effective area of ​​the irradiation module is affected by bladder volume and tumor tissue distribution, the effective area typically ranges from 1 square millimeter to 5 square centimeters. Therefore, when the bladder filling level changes, the difference in elastic recovery speed may cause some light to irradiate normal tissue areas outside the tumor tissue.

[0035] Based on the impact of bladder deformation on the physical distance between the bladder and the illumination module, this paper proposes a device that adjusts the illumination module's power and / or distance from the bladder wall according to bladder fullness, thereby calibrating the illumination pattern applied to the bladder. This calibration pattern dynamically adjusts the illumination module's power or illumination duration in response to the body's metabolic processes, thereby improving the accuracy of photodynamic therapy within a single treatment session.

[0036] The irradiation time is determined based on the accumulation of the photosensitizer in the bladder cancer cells and its absorption characteristics of blue light. Preferably, the irradiation time is adjusted based on the wavelength shift of the light emitted by the irradiation module in the liquid pharmaceutical composition.

[0037] The duration of drug infusion directly affects the amount of fluid accumulated in the bladder, thereby changing the degree of bladder filling. By controlling the degree of filling, the present invention can optimize the drug's residence time in the bladder, enabling it to achieve energy absorption during the illumination period and accelerate cell oxidative apoptosis during the window period in conjunction with an intermittent illumination mode.

[0038] The illumination module is an LED lamp or a laser device with selective wavelength output. Preferably, the illumination module can provide pulsed light.

[0039] Compared to conventional light irradiation, pulsed light can generate higher peak power in a short period of time, allowing photosensitizers to be activated more quickly and effectively, thereby enhancing the speed and efficiency of target cell oxidative apoptosis under pulsed light. At the same time, pulsed light provides short bursts of high-energy light followed by longer intervals. This intermittent light delivery provides tumor tissue with time to replenish and restore its oxygen levels after each pulse.

[0040] The illumination module is controlled by a central control unit and the light generated is operated in an optically transparent medium so that the light can be evenly distributed and penetrate the entire bladder.

[0041] The optically transparent medium ensures uniform light distribution, which helps to evenly activate the photosensitizer in various areas of the bladder and improve the treatment effect. In particular, for photodynamic therapy of the superficial mucosal layer, uniform distribution of light effect, or even distribution of light energy, is important for reducing light loss, increasing the treatment range, and reducing radiation loss to normal tissue.

[0042] Before and after light exposure, the patient's bladder needs to be flushed to remove excess drug composition and its metabolites.

[0043] In order to reduce unnecessary photochemical reactions, reduce the metabolites of potential toxic reactions, and reduce interference with subsequent photodynamic therapy, the bladder of the patient who cooperates with the system for photodynamic therapy in the present invention is in a clean state before and after treatment to improve the specificity and effectiveness of the treatment and ensure the safety of the patient.

[0044] The system also includes a second monitoring module with a function of detecting the singlet oxygen concentration in the patient's bladder in real time, wherein the central control unit adjusts the illumination intermittent frequency of the illumination module based on changes in the singlet oxygen concentration function.

[0045] In photodynamic therapy, photosensitizers are activated by light of a specific wavelength, generating singlet oxygen. Singlet oxygen oxidatively damages key cellular structures such as cell membranes, mitochondria, and nucleic acids, leading to apoptosis or necrosis of tumor cells. As a high-energy, reactive oxygen molecule, the rate at which singlet oxygen is generated and consumed in cells is crucial to the effectiveness of treatment.

[0046] By real-time monitoring of singlet oxygen concentration in the bladder, the present invention enables the system to precisely control the activation level of the photosensitizer, ensuring sufficient singlet oxygen generation in the local environment for maximum tumor cell destruction. Furthermore, to ensure that effective singlet oxygen concentrations are maintained throughout treatment and to avoid the effects of excessive or insufficient singlet oxygen, real-time monitoring of singlet oxygen concentrations in the bladder provides a reference for the central control unit to adjust the intermittent frequency of illumination.

[0047] The detection area of ​​the second monitoring module can be the diseased tissue in the lesion area of ​​the bladder wall. To meet the need to increase the singlet oxygen concentration in cells during treatment, the central control unit can calculate the pulse frequency when the patient is at different singlet oxygen concentrations based on light intensity, drug concentration, and oxygen concentration. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is a schematic diagram of hardware connections of a preferred photodynamic therapy system provided by the present invention;

[0049] Figure 2 Schematic diagram of the treatment process of the photodynamic therapy system provided by the present invention;

[0050] Figure 3 This is a schematic diagram of a usage scenario of the photodynamic therapy system provided by the present invention;

[0051] Figure 4 This is a schematic diagram of the photodynamic therapy system provided by the present invention in use;

[0052] Figure 5 is a schematic diagram of a three-dimensional treatment response surface provided by the present invention;

[0053] Figure 6 This is a hardware connection diagram of another preferred photodynamic therapy system provided by the present invention;

[0054] Figure 7 This is a flow chart of another preferred photodynamic therapy system provided by the present invention.

[0055] Reference Signs List

[0056] 100: treatment catheter assembly; 110: irradiation module; 120: first monitoring module; 130: second monitoring module; 200: central control unit. DETAILED DESCRIPTION

[0057] The following is a detailed description with reference to the accompanying drawings.

[0058] Example 1

[0059] like Figure 1As shown, the present invention discloses a photodynamic therapy system for treating bladder cancer, which includes: a treatment catheter assembly 100 for performing laser energy delivery and biosensor signal acquisition operations on a bladder lesion area, and a central control unit 200 for performing data processing and control signal generation. The central control unit 200 and the treatment catheter assembly 100 can adopt a split physical architecture design, so that the central control unit 200 can be connected to the proximal interface of the treatment catheter assembly 100 via a bus, and send signals including laser power adjustment instructions, mechanical motion control signals and / or fluid perfusion parameters to the treatment catheter assembly 100 via the bus, while simultaneously receiving multimodal biophysical data such as oxygen partial pressure, temperature and / or position fed back by the embedded sensor of the treatment catheter assembly 100 in real time, forming a "decision-execution-feedback" dynamic control loop to ensure precise delivery of light dose and synchronous optimization of biological response during the treatment process. Preferably, the central control unit 200 can be placed externally inside the treatment cart as an independent master control device, connected to the proximal interface of the treatment catheter assembly 100 via a medical-grade multi-core hybrid cable (containing optical fiber channels and electrical signal lines); the functional modules within the treatment catheter assembly 100 can be integrated with the proximal interface via a flexible circuit board embedded in the catheter wall, forming a unified physical connection point. This design not only ensures the lightweight and operational flexibility of the treatment catheter assembly 100, but also enables rapid plug-in and unplugging of the central control unit 200 and the treatment catheter assembly 100 through a modular interface, while also meeting the insulation and electromagnetic compatibility requirements of medical electrical equipment.

[0060] Preferably, the central control unit 200 can process the raw data from each sensor (especially the sensors configured in each functional module of the treatment catheter assembly 100) in real time, and its hardware interface can include 4 fiber optic channels (for laser control), 2 Camera Link interfaces (for imaging data transmission) and 1 MIL-STD-1553B bus (for medical equipment-level communication). In terms of safety design, three levels of electrical isolation can be set up inside the central control unit 200: the sensor signal enters the ADC module after optical coupling isolation, the power control signal is output through the magnetic isolation driver, and the emergency stop circuit uses an independent 48V DC power supply. The central control unit 200 is connected to each module through a customized backplane, and the backplane integrates an impedance matching circuit to ensure that the signal attenuation is less than 0.1dB within a distance of 2m. Data storage uses a dual redundant RAID1 array to record various parameters during the treatment process in real time.

[0061] Preferably, the treatment catheter assembly 100 serves as a physical interaction terminal between the system and biological tissue, and may include one or more of the following functional modules: an irradiation module 110, for irradiating the bladder lesion area; a first monitoring module 120, for measuring the oxygen partial pressure distribution data of the tumor tissue in the bladder lesion area in real time; and a second monitoring module 130, for capturing and quantifying the spatial distribution of singlet oxygen during photodynamic therapy.

[0062] Preferably, the therapeutic catheter assembly 100 can be designed with a multi-layer composite structure, with a core layer consisting of multimode quartz optical fiber coated with a fluorinated ethylene propylene copolymer buffer layer. The second layer consists of multiple independent cavities, including optical fiber bundles and cables for signal transmission, drug infusion channels, and vacuum suction channels. The inner wall of the drug infusion channel is treated with a special coating, and the vacuum suction channel is designed with spiral grooves to optimize fluid flow. The third layer is a flexible reinforced structure wrapped with a nickel-titanium alloy wire mesh and covered with a polyurethane elastic sheath for mechanical protection. The tip of the therapeutic catheter assembly 100 integrates a spherical diffuser lens group, which is driven by a micromotor for angle adjustment and is equipped with an atomizing nozzle for drug delivery. A multi-channel rotary joint is provided at the proximal end of the therapeutic catheter assembly 100 to ensure that the various functions of the catheter remain stably connected during rotation. The drug infusion channel is connected to a micropump for precise flow control, and all metal components are treated for biocompatibility. Preferably, the treatment catheter assembly 100 may not be configured with a drug infusion channel and a negative pressure suction channel, so that the drug composition containing the photosensitizer can be infused into the bladder once through other infusion devices (such as a urinary catheter) before treatment.

[0063] Preferably, the irradiation module 110 can adopt a distributed fiber coupling architecture, and the core components are three groups of wavelength-locked semiconductor laser arrays, each group can contain 12 laser diodes with an output power of 5W, and the spectrum of the therapeutic light and the excitation light is superimposed through a wavelength combiner. The laser head has an integrated microchannel liquid cooling system, which adopts deionized water circulation cooling and is equipped with a redundant temperature sensor (PT1000 platinum resistance, accuracy of ±0.1°C). When the chip temperature exceeds 45°C, the output power is automatically reduced. The irradiation module 110 can be connected to the treatment catheter assembly 100 through an armored optical fiber bundle, and a mechanical interlocking device is provided at the optical fiber interface to ensure that the laser output is immediately cut off when the catheter is detached. In terms of power regulation, pulse width modulation (PWM) and current regulation dual-mode control are adopted, and the RS485 instruction sent by the central control unit 200 can be used to control the power supply between 50 and 200 mW / cm 2The system achieves 0.1mW precision adjustment within a wide range. A built-in closed-loop optical power feedback system uses a back-facing photodiode to correct output fluctuations in real time. This closed-loop optical power feedback system includes a power monitoring unit. After the total power output from the irradiation module 110 is split by a fiber coupler, 99% of the power is transmitted to the treatment catheter assembly 100, and the remaining 1% is transmitted back to the power monitoring unit via a feedback fiber. This unit is directly connected to the irradiation module 110's driver circuit via an analog signal, forming a closed-loop control circuit to ensure therapeutic dose stability.

[0064] Preferably, the first monitoring module 120 can be composed of a multi-spectral fluorescence detection unit, the core of which is a ring-shaped fiber optic oxygen sensor array embedded in the front end of the treatment catheter assembly 100. Formenti F, Chen R, McPeak H et al. published an article in Respir Physiol Neurobiol in 2014 titled "Afibre optic oxygen sensor that detects rapid PO2 changes under simulated conditions of cyclical atelectasis invitro". The study showed that fiber optic oxygen sensors can detect rapid PO2 changes, are suitable for clinical use, and have high precision characteristics, suitable for dynamic monitoring. Furthermore, the sensor array uses six groups of 0.6mm diameter sapphire fiber probes, each of which is coated with a ruthenium (II)-tris (4,7-diphenyl-1,10-phenanthroline) fluorescent coating at the end. The local tissue oxygen partial pressure (PO2) data is calculated by measuring the decay characteristics of the fluorescence lifetime in the range of 10 to 100μs. The sensor array is connected to the central control unit 200 via a 24-core shielded cable and uses time-division multiplexing (TDM) technology to achieve six-channel synchronous sampling at a sampling rate of 100 Hz. Mechanically, the probes are embedded in the catheter wall in a spiral arrangement, with a 2mm spacing between adjacent probes to ensure constant contact pressure even when the catheter is bent. The calibration system includes a built-in reference chamber that automatically performs zero-point calibration (nitrogen environment) and full-scale calibration (air environment) every 30 minutes, ensuring a measurement accuracy of ±1.5 mmHg during long-term treatment.

[0065] Preferably, the second monitoring module 130 can realize singlet oxygen ( 1 O2) monitoring, wherein the available sampling methods include phosphorescence monitoring method, fluorescence monitoring method, etc. Singlet oxygen releases characteristic phosphorescence when it decays, with a wavelength of about 1270nm. Therefore, the second monitoring module 130 using the phosphorescence monitoring method can directly detect 1The physical properties of O2 do not require chemical probes. Tian W, Deng L, Jin S et al. published an article titled "Singlet oxygen phosphorescence lifetime imaging based on a fluorescence lifetime imaging microscope" in J Phys Chem A in 2015. The study showed that phosphorescence lifetime imaging can monitor the 1 The technology of O2 spatial distribution has high resolution and has been used for single cell and in vivo imaging studies. The second monitoring module 130 using fluorescence monitoring method can be configured with a fluorescent probe, which 1 O2 undergoes chemical reactions to produce fluorescent signal changes. Weiying Hou, Ye Yuan, Zezhou Sun et al. published an article titled "Ratiometric Fluorescent Detection of Intracellular Singlet Oxygen by Semiconducting Polymer Dots" in the American Chemical Society on November 22, 2018. The study showed that fluorescent probes can be used to monitor intracellular singlet oxygen in real time during photodynamic therapy. 1 Dynamic generation of O2.

[0066] Preferably, if Figures 2 to 4 As shown, when the photodynamic therapy system of the present invention is working, the treatment catheter assembly 100 can first be introduced into the patient's bladder (through the urethra) and accurately positioned to the bladder lesion area, and then the central control unit 200 can send an initialization instruction to the treatment catheter assembly 100, wherein the initialization of the treatment catheter assembly 100 may include perfusing the bladder lesion area with a drug composition containing a photosensitizer through a drug perfusion channel, and at the same time, the initialization of the first monitoring module 120 and the second monitoring module 130 can be completed. The central control unit 200 can first obtain the oxygen partial pressure distribution data of the tumor tissue through the first monitoring module 120 of the treatment catheter assembly 100, and use the built-in reference chamber to complete the sensor zero point calibration. During the initialization stage, the irradiation module 110 can output the detection light beam according to the preset parameters. At this time, the central control unit 200 can receive the oxygen partial pressure data from the first monitoring module 120, and calculate the oxygen recovery time constant in combination with the following formula

[0067]

[0068] Where V t is the tumor volume; D eff is the effective diffusion coefficient, which can be obtained by Calculated, Ht is the tumor heterogeneity index, and its exponential form describes the tumor heterogeneity index H t Inhibitory effect on oxygen transport capacity; and These are respectively the highest oxygen partial pressure and the lowest oxygen partial pressure of the tumor tissue in the bladder lesion area acquired by the first monitoring module 120 .

[0069] In the above formula, the tumor heterogeneity index H t It can be obtained by matching with the pathology database, which quantifies the blocking effect of the degree of vascular distribution disorder inside the tumor on oxygen diffusion; V t 2 / 3 This reflects the correlation between oxygen diffusion path length and tumor geometry, consistent with the fundamental principles of tumor oxygen diffusion models (e.g., in the article "Pulsation-limited oxygen diffusion in the tumor microenvironment" by Milotti, E., Stella, S., and Chignola, R., published in Scientific Reports in 2017). This formula, derived from Fick's diffusion law and research on oxygen dynamics in the tumor microenvironment, aims to upgrade the traditional fixed intermittent cycle to a spatially adaptive dynamic control. By calculating the time required for oxygen recovery in different regions in real time, it avoids the loss of treatment efficiency caused by localized hypoxia. The results of this formula serve as input parameters for the adaptive intermittent control algorithm to dynamically generate treatment parameter combinations.

[0070] Preferably, if Figures 2 to 4 As shown, after entering the treatment phase, the central control unit 200 can generate a pulse width modulation signal based on the built-in adaptive intermittent control algorithm to drive the irradiation module 110 to perform adaptive intermittent irradiation on the bladder lesion area. When the irradiation module 110 irradiates the bladder lesion area, the second monitoring module 130 can capture the phosphorescence signal and / or fluorescence signal, and then send it to the central control unit 200 for data processing to obtain 1 O2 concentration.

[0071] Preferably, the adaptive intermittent control algorithm built into the central control unit 200 may include the following pulse parameter dynamic equation:

[0072]

[0073] Where, T on and T off are respectively the start irradiation time and stop irradiation time of adaptive intermittent irradiation, 1 O2 is the singlet oxygen concentration.

[0074] The above formula uses a hyperbolic tangent function to constrain the laser on-irradiation time. Its design purpose is to establish a nonlinear mapping relationship between singlet oxygen concentration and on-irradiation time. When the concentration exceeds 35μM, the function asymptotically saturates to prevent excessive irradiation from causing oxygen depletion crisis. The matching calculation equation for the off-irradiation time introduces an oxygen compensation coefficient of 0.15, which is derived from the experimental results of oxygen diffusion dynamics of isolated bladder tissue. Furthermore, when the minimum oxygen partial pressure is monitored, When the oxygen level falls below 15 mmHg, the oxygen compensation mode is triggered to automatically extend the irradiation stop period (i.e., the interval period). This increases the recovery time of the hypoxic area in a positive correlation with the degree of hypoxia. When the oxygen compensation mode is triggered, the irradiation stop period is automatically extended to 1.5 to 3 times the baseline value. The above formula forms a dose-response closed-loop control through real-time feedback, ensuring that the photosensitizer is fully activated while avoiding oxygen resource depletion caused by continuous irradiation.

[0075] Preferably, the central control unit 200 can also adjust the deflection angle of the spherical diffusion lens at the tip of the treatment catheter assembly 100 by generating a mechanical motion control signal, so that the laser energy can be refocused on the area with higher oxygen partial pressure.

[0076] Preferably, during the treatment process, the central control unit 200 may perform a three-dimensional treatment response surface reconstruction every preset time to optimize the treatment process, wherein the central control unit 200 may perform a three-dimensional treatment response surface reconstruction every preset time to optimize the treatment process, wherein the central control unit 200 may perform a three-dimensional treatment response surface reconstruction by using the oxygen enhancement factor Updated treatment effectiveness index for each region The therapeutic efficacy index is used to quantify the therapeutic effectiveness of a certain area under a specific oxygen partial pressure and pulse timing, so that the central control unit 200 can adjust the interval length and / or the applied light parameters based on the changes in the therapeutic efficacy index. The light parameters may include the light intensity (i.e., light intensity, which can also be power density) and / or wavelength of the laser. and therapeutic efficacy index The calculation formula is as follows:

[0077]

[0078] Where, is the average oxygen partial pressure; E eff It is a benchmark treatment efficacy index, which is related to the initial light parameters (such as light intensity and wavelength) and treatment time (such as interval length); is the intermittent time ratio correction term, which represents the improvement of treatment efficiency during the oxygen recovery phase.

[0079] The oxygen enhancement factor introduced in the reconstruction of the three-dimensional treatment response surface converts the average oxygen partial pressure into a therapeutic effect correction coefficient through a smooth transition function. When the average oxygen partial pressure in a certain area exceeds 22 mmHg, the oxygen enhancement factor approaches 1, and the original therapeutic efficacy index is completely retained; when it is below this threshold, the nonlinear characteristics of the tanh function make Rapid decay, retaining at least 80% of the basic therapeutic effect. This design is based on the nonlinear relationship between oxygen partial pressure and therapeutic effect found in clinical observations. Its function is to overcome the efficiency loss of the traditional uniform energy delivery mode in the hypoxic area (that is, the area where the oxygen enhancement factor is lower than the preset threshold), so that the system can implement differentiated energy regulation according to the oxygen distribution gradient. The therapeutic efficacy index formula further integrates the intermittent time ratio parameter, and its intermittent time ratio correction term dynamically links the oxygen recovery time with the treatment efficiency. Its function is to convert the pulse timing parameters into an efficacy gain factor. When the system is triggered by hypoxia to extend the intermittent period (T off Increase), the interval time ratio correction term approaches 1, prompting the central control unit 200 to send a control instruction to increase the ramp rate of the laser power in the next cycle after the oxygen recovery stage, thereby effectively capturing the therapeutic benefits brought by extending the oxygen recovery time. At the same time, the spherical diffusion lens group at the tip of the treatment catheter assembly 100 can also be used to adjust the spot coverage range to ensure that the energy is concentratedly delivered to the area where the oxygen partial pressure recovery meets the standard.

[0080] Preferably, at the three-dimensional spatial control level, the oxygen enhancement factor and the therapeutic efficacy index together constitute the weight matrix of the therapeutic response surface. The central control unit 200 can generate three-dimensional point cloud data in real time according to the light intensity, duration and therapeutic efficacy index, thereby forming a three-dimensional therapeutic response surface, such as Figure 5 When the therapeutic efficacy index of a tumor region falls below a set threshold, the central control unit 200 triggers multiple adjustments in the treatment catheter assembly 100, including: using a micromotor to drive the tip lens of the treatment catheter assembly 100 to change the illumination angle (adjustable within ±15°), shifting the center of the light spot toward an adjacent area with a higher oxygen partial pressure; and / or adjusting the illumination parameters corresponding to that area.

[0081] Preferably, the central control unit 200 calculates the oxygen enhancement factor in real time and therapeutic efficacy index After that, you can perform one or more of the following adjustments:

[0082] (1) When the therapeutic efficacy index If the laser intensity (or power density) of the laser in the area decreases (such as due to hypoxia or insufficient intermittent therapy), the central control unit 200 can increase the laser intensity (or power density) in that area proportionally to compensate for the loss of therapeutic effect. The compensation ratio can be based on the current (latest) therapeutic efficacy index. and baseline treatment efficacy index E effFor example, the original light intensity (or power density) is divided by the above ratio (i.e. ) to obtain the adjusted light intensity (or power density).

[0083] (2) For low oxygen areas (such as ), the central control unit 200 can increase the proportion of therapeutic light (penetrate deeper) and reduce the proportion of excitation light (reduce surface oxygen consumption).

[0084] (3) Based on the reconstructed three-dimensional treatment response surface, the high treatment efficacy index The spot residence time in the area is prolonged and the inefficient area is shortened.

[0085] For example, when a patient is treated clinically with the photodynamic therapy system of the present invention, the tumor tissue-related parameters of the bladder lesion area are: the baseline light intensity of the laser = 150mW / cm 2 ; Real-time average oxygen partial pressure = 18mmHg; Interval time ratio T off / T on =2.0. From this we can calculate: oxygen enhancement factor Interval time ratio correction term ≈ 0.75, treatment efficacy index Based on the above calculation results, the central control unit can perform one or more of the following adjustment methods:

[0086] (1) Increase the light intensity (e.g. adjust to 224mW / cm 2 );

[0087] (2) Increase the proportion of therapeutic light (e.g., from 70% to 85%);

[0088] (3) Compared with the therapeutic efficacy index of other areas, the light spot stays in the area with high therapeutic efficacy index for a longer time.

[0089] Preferably, when performing adjustments, the central control unit 200 may establish a dynamic adjustment mechanism for the safety threshold value that is dependent on the oxygen partial pressure based on a preset safety constraint equation group, wherein the safety constraint equation group may include:

[0090]

[0091] In the formula, [ 1 O2] peak is the peak concentration of singlet oxygen monitored in real time during treatment; PO2 is the real-time oxygen partial pressure; ΔT 黏膜 The temperature rise of the mucosal surface during treatment can be measured by infrared thermal imaging or embedded micro-thermocouples.

[0092] In the above equations, the first equation relates the singlet oxygen peak concentration limit to the real-time oxygen partial pressure (in a nonlinear negative correlation), automatically reducing the maximum allowed value when tissue hypoxia occurs. 1 O2 concentration to prevent photosensitivity reactions from excessively consuming residual oxygen and leading to cytotoxicity (i.e., phototoxic overload); the second equation dynamically binds the mucosal temperature rise limit to the minimum oxygen partial pressure (dynamic linear relationship), and relaxes the temperature control threshold by 0.1℃ / mmHg under hypoxic conditions (PO2<25mmHg). This design is based on the physiological characteristics of the decreased heat dissipation capacity of hypoxic tissue, and avoids treatment interruption caused by overly conservative temperature control while ensuring safety.

[0093] Preferably, based on the preset safety constraint equations, the central control unit 200 may have the following multi-level safety logic hierarchy:

[0094] (1) Primary constraints:

[0095] when[ 1 O2] peak When the dynamic threshold is exceeded, the laser output is immediately cut off (response time < 50ms);

[0096] When ΔT 黏膜 When the limit is exceeded, the liquid cooling flooding operation is enabled.

[0097] (2) Secondary strategy:

[0098] When the constraint is triggered three times in a row, the interval is automatically extended to 200% of the original value;

[0099] Adjust the light spot scanning path to avoid high-risk areas.

[0100] Example 2

[0101] This embodiment provides a photodynamic therapy method, which uses blue light to excite a pharmaceutical composition containing hipoxin for oxidative killing of tumor tissue.

[0102] like Figure 7 As shown in the flowchart, the photodynamic therapy method may include the following steps:

[0103] (a) injecting a pharmaceutical composition containing Xibofen into the patient's bladder;

[0104] (b) a period of time to allow Hibacterium to accumulate in bladder cancer cells;

[0105] (c) irradiating the interior of the patient's bladder with blue light using a light source having a wavelength in the range of 400 to 700 nanometers at an intensity of 1.5 to 12.5 milliwatts per square centimeter for a predetermined period of time;

[0106] (d) The light intensity and irradiation time are selected to be sufficient to activate Hipoxin to generate sufficient amounts of reactive oxygen species to kill bladder cancer cells without causing significant damage to surrounding healthy tissues.

[0107] Preferably, the injection of the pharmaceutical composition can be perfusion, intravenous injection or microneedle injection. Suitable patients include patients with urothelial carcinoma (transitional cell carcinoma), squamous cell carcinoma, adenocarcinoma, sarcoma or small cell carcinoma.

[0108] Preferably, "a certain period of time has passed to allow the accumulation of Hipoxin in bladder cancer cells" means that the inner layer of the bladder (especially the inner layer where the tumor grows) absorbs and accumulates a sufficient amount of Hipoxin. The "certain period of time" is related to the patient's disease type, tumor tissue size and / or injection amount. The "certain period of time" can be confirmed based on relevant detection equipment. For example, the detection equipment can detect the fluorescence expression level of the bladder inner layer. When the fluorescence expression level reaches a certain preset value, it means that the amount of Hipoxin accumulated in the bladder inner layer meets the light irradiation conditions.

[0109] Preferably, the illumination wavelength band can be between 400 and 700 nanometers to cover a variety of light wavelength bands that can effectively activate Hibofen. Red light (about 600-700 nanometers) is particularly suitable for treating deeper lesions due to its strong penetrability, such as lesion tissue infiltrating into the mucosal layer (i.e., tumor tissue). Blue light (about 400-450 nanometers) has a relatively short wavelength and a shallow penetration depth, and is usually used to treat superficial lesions, such as lesion tissue distributed in the serosal layer (i.e., tumor tissue). The penetration depth of green light (about 500-570 nanometers) is between that of blue light and red light, and is mainly used for some lesions between the superficial and middle depths, such as lesion tissue infiltrating into the muscle layer (i.e., tumor tissue).

[0110] The irradiation is intermittent, that is, the blue light is irradiated at a preset intensity for a preset time every few minutes.

[0111] Preferably, the intermittent irradiation is implemented by, for example, irradiating for 1 to 5 minutes every 5 to 10 minutes; or irradiating for 5 to 10 minutes every 10 to 20 minutes; or irradiating for 10 to 15 minutes every 20 to 30 minutes.

[0112] Example 3

[0113] This embodiment relates to a light irradiation method for photodynamic therapy of bladder cancer and a photodynamic therapy system for dynamically adjusting light intensity.

[0114] like Figure 6 、 Figure 7As shown, an operator can handhold an endoscope equipped with the illumination module 110 of the present invention and insert it into the patient's bladder through the patient's urethra. Based on instructions from the central control unit 200, light of a preset wavelength is provided inside the patient's bladder. This light is used to combine with a photosensitizer to generate reactive oxygen species. An example of the photosensitizer is hypocretin.

[0115] Specifically, the illumination intensity of the irradiation module 110 is controlled by the central control unit 200 adjusting the power of the irradiation module 110 and / or the distance between the patient's bladder and the irradiation module 110, wherein the distance between the patient's bladder and the irradiation module 110 is calibrated according to the degree of bladder filling caused by the injection of the pharmaceutical composition containing the photosensitizer.

[0116] The central control unit 200 can control the illumination intensity by adjusting the power of the illumination module 110 .

[0117] like Figure 6 As shown, the system includes a drug administration module. The drug administration module can be a device or an intravenous injection device that instills photosensitizer into the patient's bladder based on a preset dosage.

[0118] According to a preferred embodiment, the drug delivery module can also be a microneedle assembly. After entering the bladder, the microneedle assembly can inject the photosensitizer at a predetermined location. In the prior art, the accumulation of photosensitizers in tumor cells and healthy cells depends on the absorption differences between tumor and healthy cells. However, due to the permeability of the serosal layer, instilling the photosensitizer into the muscle layer prevents it from penetrating deeply into the bladder. Intravenous injection of photosensitizers reduces the accumulation of photosensitizers in the bladder and reduces its efficacy. Based on this, the drug delivery module of the present invention can be configured as a microneedle assembly. The microneedle assembly is used to inject the photosensitizer pharmaceutical composition into the bladder. The microneedle assembly needs to be biocompatible, and its length and diameter need to be configured based on the penetration level of the photosensitizer. The depth of the photosensitizer injection in the microneedle assembly can be customized based on the treatment needs. For example, this depth can be the mucosal layer, muscle layer, or serosal layer of the patient's bladder. The microneedle assembly can also be customized based on the treatment needs. The location of the photosensitizer injection can be the trigone, fundus, or apex of the bladder. For example, a tumor may be concentrated in the serosal layer on the right side of the bladder and infiltrate the muscle layer. The microneedle assembly can increase the amount of photosensitizer injected into the right bladder serosal layer during the initial treatment. In subsequent treatments, as the number of tumors in the serosal layer decreases, the microneedle assembly can penetrate deeper into the muscle layer and inject photosensitizer there to increase the efficiency of eliminating tumors in the muscle layer.

[0119] The irradiation module 110 is equipped with a light source, a light controller for adjusting the light source power, and a distance controller for adjusting the relative position of the light source and the patient's bladder. In this embodiment, the central control unit 200 is connected to the built-in light controller and distance controller via a wired or wireless connection. The central control unit 200 sends signals to the light controller or distance controller to adjust the light source power or the relative position between the light source and the patient's bladder. Preferably, the light source is a blue light source. The light controller can be a light intensity regulator.

[0120] Specifically, in treatment mode, the light source is turned on. After completing the initial settings, the operator can manipulate the irradiation module 110 or the endoscope equipped with the irradiation module 110 to insert into the patient's bladder. Figure 4 As shown, after entering the bladder, the irradiation module 110 can partially or completely irradiate the inner layer of the bladder. The inner layer includes a mucosal layer, a muscle layer, and a serous layer.

[0121] During operation, the central control unit 200 can dynamically adjust the light intermittent mode (eg, pulse frequency) based on the amount of photosensitizer injected, the state of tumor cells (phenotype related to singlet oxygen transport rate), and / or singlet oxygen production feedback.

[0122] The central control unit 200 is configured to determine the pulse frequency based on formula (1):

[0123]

[0124] Where I represents the light intensity in mW / cm 2 ; D represents drug concentration, unit is M, which is a preset value; O represents oxygen concentration, unit is M, which is monitored in real time or is a preset value; S current Indicates the current singlet oxygen concentration in M, which is obtained through a fluorescent probe or other real-time detection equipment; S target represents the target singlet oxygen concentration, the unit is M, which is the target value set according to the treatment plan; f represents the pulse frequency, the unit is Hertz (Hz).

[0125] Based on the patient's initially set target singlet oxygen concentration, light intensity, and drug concentration, the central control unit 200 generates a corresponding pulse frequency according to the dynamic changes in the singlet oxygen concentration. For example, as shown in Table 1, for patients with recurrent lesions or residual lesions, a standard dose (e.g., local microneedle injection of 25 mg of Hipoxetine) is used; for patients with initial lesions, an enhanced dose (e.g., local microneedle injection of 50 mg of Hipoxetine) is used. For tumor tissue that has entered the muscle layer or mucosal layer, a high-efficiency light source is used when targeting the tumor tissue, while a conventional light source is used when targeting the serosal tumor tissue. The light intensity is adjusted based on the concentration of the photosensitizer, for example, 0.05 to 0.1 W / cm 2Considering the intensity of active oxygen in disinfecting tumors, the drug concentration is adjusted. For example, for transitional cell carcinoma (TCC), a photosensitizer with a first drug concentration (e.g., 1×10 -6 M); Squamous cell carcinoma (SCC) can use a second drug concentration of photosensitizer (for example, 2×10 -6 M). Furthermore, oxygen supply to the bladder lining should also be considered during photodynamic therapy. Oxygen supply to the bladder lining is a crucial factor influencing photodynamic therapy. The core mechanism of photodynamic therapy is the generation of reactive oxygen species (such as singlet oxygen) by photosensitizers under the stimulation of light of a specific wavelength. These reactive oxygen species are capable of destroying tumor cells. The oxygen content in the tissues of the targeted area directly affects the efficiency of tumor cell destruction.

[0126] Table 1

[0127] Cross-experiment parameter table

[0128]

[0129] As shown in Table 1, when using standard dose, conventional light source, and light intensity of 0.05W / cm 2 , the drug concentration was 1×10 -6 When M is used as the initial photodynamic therapy solution, based on the preset target singlet oxygen concentration (e.g., 5×10 -6 M), and a first pulse frequency (e.g., 0.67 Hz) is calculated using formula (1) based on the real-time monitored singlet oxygen concentration. When the oxygen concentration is lower than the instruction generated by the central control unit 200, the irradiation module 110 provides photodynamic therapy to the bladder inner layer at the first pulse frequency.

[0130] The central control unit 200 controls the pulse frequency of the irradiation module 110 to 0.67 Hz in real time, so that the system can continuously adjust and ensure that the singlet oxygen concentration in the tumor cells in the patient's bladder is within the target range, so that the photodynamic therapy effect is always not affected by oxygen deficiency (which causes the reactive oxygen species to fail to kill cells).

[0131] Furthermore, in response to the need to increase the singlet oxygen concentration in the cells during treatment, the central control unit 200 can calculate the pulse frequency when the patient is at different singlet oxygen concentrations based on the light intensity, drug concentration, and oxygen concentration. Preferably, the light intensity, drug concentration, and oxygen concentration are initial setting parameters. For example, when the singlet oxygen concentration is lower than the minimum endpoint value of the first range, the pulse frequency can be obtained using formula (2):

[0132]

[0133] Where I represents the light intensity, the unit is W / cm 2 ; D represents drug concentration, unit is M, which is a preset value; O represents oxygen concentration, unit is M, which is monitored in real time or preset value; S current Indicates the current singlet oxygen concentration in M, which is obtained through a fluorescent probe or other real-time detection equipment; S target represents the target singlet oxygen concentration, in M, which is the target value set according to the treatment plan; f low is the pulse frequency when the singlet oxygen concentration is lower than the minimum endpoint value of the first range, and its unit is Hertz (Hz); α and β are control constants used to adjust the dark time and light time.

[0134] When the singlet oxygen concentration is in the first range, the pulse frequency can be obtained using formula (3):

[0135]

[0136] Where I represents the light intensity, the unit is W / cm 2 ; D represents drug concentration, unit is M, which is a preset value; O represents oxygen concentration, unit is M, which is monitored in real time or preset value; S current Indicates the current singlet oxygen concentration in M, which is obtained through a fluorescent probe or other real-time detection equipment; S target represents the target singlet oxygen concentration, in M, which is the target value set according to the treatment plan; f medium is the pulse frequency when the singlet oxygen concentration is in the first range, and its unit is Hertz (Hz); γ and δ are control constants.

[0137] When the singlet oxygen concentration is higher than the maximum endpoint value of the first range, the pulse frequency can be obtained using formula (4):

[0138]

[0139] Where I represents the light intensity, the unit is W / cm 2 ; D represents drug concentration, unit is M, which is a preset value; O represents oxygen concentration, unit is M, which is monitored in real time or preset value; S current Indicates the current singlet oxygen concentration in M, which is obtained through a fluorescent probe or other real-time detection equipment; S target represents the target singlet oxygen concentration, in M, which is the target value set according to the treatment plan; f high is the pulse frequency when the singlet oxygen concentration is higher than the maximum endpoint value of the first range, and its unit is Hertz (Hz); ∈ and ζ are control constants.

[0140] The central control unit 200 is provided with a storage component for storing historical data or data input by medical personnel, as shown in Table 2.

[0141] When the singlet oxygen concentration is lower than the minimum endpoint value of the first range, the initial preset drug concentration is 1×10 -6 M, light intensity is 0.5W / cm 2 When α is 1.2 and β is 1.5; or when the singlet oxygen concentration is lower than the minimum endpoint of the first range, the initial preset drug concentration is 2×10 -6 M, light intensity is 1W / cm 2 When α is 1.0 and β is 1.3, the central control unit 200 generates an instruction to adjust the pulse frequency of the irradiation module 110 based on formula (2).

[0142] When the singlet oxygen concentration is in the first range, the initial preset drug concentration is 1×10 -6 M, light intensity is 0.5W / cm 2 When γ is 1.1 and δ is 1.3; or when the singlet oxygen concentration is in the first range, the initial preset drug concentration is 2×10 -6 M, light intensity is 1W / cm 2 When γ is 0.9 and δ is 1.1, the central control unit 200 generates an instruction to adjust the pulse frequency of the irradiation module 110 based on formula (3).

[0143] When the singlet oxygen concentration is higher than the maximum endpoint value of the first range, the initial preset drug concentration is 1×10 -6 M, light intensity is 0.5W / cm 2 When ∈ is 0.9 and ζ is 1.2; or when the singlet oxygen concentration is higher than the maximum endpoint value of the first range, the initial preset drug concentration is 2×10 -6 M, light intensity is 1W / cm 2 When ∈ is 0.7 and ζ is 1.0, the central control unit 200 generates an instruction to adjust the pulse frequency of the irradiation module 110 based on formula (4).

[0144] Table 2

[0145]

[0146] The second monitoring module 130 for measuring the singlet oxygen concentration involved in the present invention can be a fluorescent probe detection device, a two-photon excitation fluorescence microscope or a near-infrared spectroscopy technology device. Specifically, the fluorescent probe is introduced into the bladder cavity through bladder lavage or other non-invasive methods, and the second monitoring module 130 can detect changes in the fluorescence signal through a fluorescent endoscope component set on the endoscopic probe. The two-photon excitation fluorescence microscope uses two beams of low-energy photons to simultaneously excite fluorescent dyes, which can reduce tissue damage and increase imaging depth. The endoscopic probe equipped with a two-photon microscope is introduced into the bladder through the urethra, and with the help of its optical fiber probe (two-photon microscope component) reaches the surface of the bladder, and uses the two-photon microscope to detect the fluorescence signal of singlet oxygen. Near-infrared spectroscopy technology uses the penetrability of near-infrared light to detect spectral changes of specific molecules in tissues. The concentration of singlet oxygen is indirectly detected by measuring the spectral changes of bladder tissue non-invasively through the near-infrared spectrometer probe.

[0147] Specifically, taking the fluorescent probe detection device as an example, by setting a fluorescent probe specifically for detecting singlet oxygen (for example, Singlet Oxygen Sensor Green), the change in fluorescence intensity is detected, and the singlet oxygen concentration is indirectly evaluated. The purpose of fluorescent detection of changes in singlet oxygen concentration can also be achieved by local injection of phosphorescent probes (using the phosphorescence lifetime characteristics of oxygen molecule quenching). At this time, the second monitoring module 130 is a specific time-resolved phosphorescence imaging device. Some biosensors can also achieve the purpose of detecting singlet oxygen in vivo. For example: some biosensors based on optical fibers or nanoparticles are embedded with fluorescent or phosphorescent probes and directly implanted near the treatment site to achieve real-time detection. For photodynamic therapy processes with long courses and long durations, the optimization scheme can use a method of local injection of optical fibers or nanoparticles directly into the inner wall of the bladder to detect singlet oxygen content. Preferably, based on a singlet oxygen nanoprobe of 1,3-diphenylisobenzofuran (DPBF) or a singlet oxygen nanoprobe doped with DPBF constructed by a reprecipitation method, the second monitoring module 130 includes a light source and a spectrometer component, which detects the concentration change of singlet oxygen by exciting the probe and receiving the absorption peak change of DPBF.

[0148] Example 4

[0149] This embodiment also relates to a photodynamic therapy system that dynamically adjusts light intensity and pulse frequency.

[0150] In photodynamic therapy, the pulse repetition frequency (PRF) refers to the frequency of pulsed light emitted by a light source, usually measured in Hertz (Hz).

[0151] In this embodiment, the time-varying singlet oxygen concentration is determined based on the rate of singlet oxygen generation and consumption, and the singlet oxygen concentration is used as a parameter for adjusting the pulse repetition frequency.

[0152] In photodynamic therapy, pulse repetition frequency (PRF) is a key parameter for regulating light intensity and temporal distribution, significantly impacting the generation, transport, and consumption of singlet oxygen, as well as its tumor-killing effect. Singlet oxygen has a limited diffusion distance, and its range of action directly affects the effectiveness of photodynamic therapy. Pulse frequency influences the tissue penetration depth of light and the amount of singlet oxygen generated. Appropriate frequency regulation facilitates the efficient diffusion of singlet oxygen within the target tissue, thereby enhancing treatment depth and overall efficacy. Furthermore, pulsed light sources excite photosensitizers through short bursts of high-intensity light, causing them to generate an excited state, which then reacts with surrounding oxygen molecules to produce singlet oxygen. The pulse frequency determines the frequency of these excitation and reaction cycles. Higher frequencies may lead to excessively frequent excited state generation of the photosensitizer, exceeding the oxygen replenishment capacity and reducing the efficiency of singlet oxygen generation.

[0153] Singlet oxygen, a key reactive oxygen molecule in photodynamic therapy, is affected by a variety of factors in its generation and concentration changes, resulting in significant variability and complexity. Specifically, the generation rate and concentration changes of singlet oxygen vary greatly in different tissue sites and individuals, making it difficult to accurately predict based on a certain pattern. For example, the transport of singlet oxygen can be affected by genetic polymorphisms, metabolic characteristics, health status, and immune status. For invasive tumor tissue, highly vascularized tumor tissue may obtain more singlet oxygen, and the area at the junction with normal tissue may also have different singlet oxygen changes due to the depth of infiltration, tumor development time, etc. Therefore, the pulse repetition frequency, an important influencing parameter of intermittent light in photodynamic therapy, needs to be adjusted in real time based on the singlet oxygen concentration at the site of action, and cannot be obtained based on regular big data statistics.

[0154] Taking the following embodiment as an example, based on the singlet oxygen net generation rate R net (t) changes with time, and the adjusted value of pulse repetition frequency PRF is generated by formulas (7) to (10). Singlet oxygen net generation rate R net (t) is obtained based on formula (5) (6).

[0155] Singlet oxygen generation rate R SO (t) can be obtained based on formula (5):

[0156]

[0157] Where I represents the light intensity, the unit is W / cm 2; C represents the drug concentration in mol / L; O represents the oxygen concentration in %; Φ represents the photochemical quantum yield (i.e., the number of molecules of singlet oxygen generated by a single photon); ∈ represents the photosensitizer extinction coefficient in L / mol·cm; d represents the light penetration depth in cm; μ a Indicates tissue absorption coefficient, unit is cm -1 ;μ s ′ represents the reduced scattering coefficient, in cm -1 ;E photon Represents the energy of a single photon, in J.

[0158] The energy of a photon depends on the wavelength of the light. Preferably, the energy of a photon corresponding to the wavelength of the near infrared light (about 700-800 nm) is photon The range is 2.48×10 -19 J (at 700 nm) to 1.55×10 -19 J (measured in 800nm).

[0159] As shown in Table 3, different types of photosensitizers have different corresponding photochemical quantum yields and extinction coefficients.

[0160] Table 3

[0161] photosensitizers Photochemical quantum yield (Φ) Extinction coefficient (∈) Porphyrin photosensitizers 0.2～0.6 <![CDATA[10 4 ~10 5 ]]> Phthalimide photosensitizers 0.1～0.5 <![CDATA[10 4 ~10 5 ]]> Phthalocyanine photosensitizers 0.3～0.7 <![CDATA[>10 5 ]]> Cyanine dyes 0.3～0.7 <![CDATA[10 5 ~10 6 ]]>

[0162] Furthermore, the net singlet oxygen generation rate R net (t) can be obtained based on formula (6):

[0163]

[0164] in, represents the consumption rate of singlet oxygen.

[0165] The change of time step length is used to simulate the change of real-time singlet oxygen concentration over time. The concentration value is updated by accumulating the net generation rate at each time step. The real-time singlet oxygen concentration is obtained according to formula (7):

[0166] SO(t+τ)=SO(t)+τ×R net (t)…(7)

[0167] Where τ represents the pulse width in seconds, and SO(t) is the singlet oxygen concentration at time t.

[0168] When comparing the real-time singlet oxygen concentration SO(t+τ) with the target concentration SO target Then, the pulse repetition frequency (PRF) adjustment formulas (8) and (9) are generated:

[0169] if(SO(t+τ) <SOtarget ) Increase the PRF new …(8)

[0170] if (SO(t + τ) ≥ SO target ) Maintain the current PRF or reduce the PRF new …(9)

[0171] PRF new = PRF current + k × (SO target - SO(t + τ))…(10)

[0172] where SO target represents the target singlet oxygen concentration in mol / L; k is the coefficient for controlling the step size of PRF adjustment.

[0173] Repeat the above steps of adjusting the PRF until |SO(t + τ) - SO target | < a, where a is the set maximum threshold of the singlet oxygen concentration.

[0174] Example 5

[0175] This example relates to a calibration system during photodynamic irradiation.

[0176] The calibration system may include a central control unit 200 that controls the light intensity by adjusting the distance between the bladder and the irradiation module 110. The distance is calibrated according to the bladder fullness, which is caused by the injection of the pharmaceutical composition.

[0177] In the bladder monitoring mode, when the fullness of the patient's bladder changes, the central control unit 200 calculates the updated power of the light source and the distance of the light source (relative to the patient's bladder) based on the change value of the fullness of the patient's bladder. Preferably, during part of the treatment process, the light intensity acting on the tumor cells can remain unchanged, but as the bladder fullness changes, the light source power and the distance of the light source need to be adjusted.

[0178] The relationship between the light intensity and the light source power can be expressed as:

[0179] I = P / A……(11)

[0180] where I represents the light intensity in mW / cm 2 ; P represents the light source power in mW; A represents the illumination area in cm 2 .

[0181] The relationship between the light intensity and the light source distance can be expressed as:

[0182] I = P / (πd 2 )……(12)

[0183] Where I represents the light intensity in mW / cm 2 ; P represents the light source power, in mW; d represents the distance between the light source and the bladder, in cm.

[0184] The greater the bladder filling, the longer it takes for the bladder to contract and the lower the light intensity. The relationship between the light source distance and the bladder filling degree can be expressed as:

[0185] d=k*V……(13)

[0186] Where d is the distance between the light source and the bladder, in cm; k is a coefficient related to the elastic deformation capacity of the bladder; and V is the degree of bladder filling, in mL.

[0187] Preferably, the degree of bladder filling is also adjusted according to the duration of infusion of the pharmaceutical composition.

[0188] The relationship between light intensity and injection duration is: the longer the injection duration, the more photosensitizer accumulates in bladder cancer cells, and the lower the required light intensity. The relationship between the two can be expressed by the following formula:

[0189] I=I0 / (t+t0)……(14)

[0190] Where I is the light intensity in mW / cm 2 ; I0 is the initial light intensity, in mW / cm 2 ; t is the injection time, unit is h; t0 is the coefficient, which is related to the type and dose of the photosensitizer.

[0191] Based on the dynamically changing bladder filling level, when the light intensity I that needs to be adjusted is obtained, the central control unit 200 can choose to adjust the light source power or light source distance according to the initially set patient bladder status, so as to ensure the illumination effect of the light source.

[0192] For example, for patients whose bladder structure is relatively fixed and whose filling level changes easily affect the light source distance (such as determined by CT or tumor staging), the central control unit 200 can calculate the adjustment distance using formulas (11) to (13) to accurately control the light distribution.

[0193] More specifically, such patients may be set to the first category. The first category may be patients with T1 stage bladder cancer in which the bladder tumor has infiltrated the bladder mucosa.

[0194] When the initially set patient category belongs to patients with limited light distribution in the bladder or affected muscle stretch, the central control unit 200 can calculate the power of the light source through formulas (11) to (13).

[0195] More specifically, such patients can be set as the second category, which can be T2 stage bladder cancer patients whose bladder tumors have invaded the bladder submucosa or T3 stage bladder cancer patients whose bladder tumors have invaded the bladder muscle layer.

[0196] Preferably, the system further includes an information input module, through which medical personnel can input the patient category. The information input module can be a keyboard, touch screen, etc. connected to the central control unit 200, which can transmit the patient category information to the central control unit 200.

[0197] According to a preferred embodiment, the distance controller can be a bending section of an endoscope. One end of the endoscope carrying the irradiation module 110 is configured to be bendable. The relative distance between the irradiation module 110 and the inner layer of the bladder is adjusted by changing the bending angle of the endoscope. Preferably, based on the confirmed relative distance between the irradiation module 110 and the inner layer of the bladder, the central control unit 200 can determine the bending angle of the endoscope using formula (15):

[0198]

[0199] Wherein, R represents the radius of the curved portion of the endoscope, which is usually known or measurable, and is expressed in mm; d represents the relative distance between the irradiation module 110 and the inner layer of the bladder, and is expressed in mm; and θ represents the bending angle of the endoscope, and is expressed in rad.

[0200] It should be noted that the above-mentioned specific embodiments are exemplary, and those skilled in the art can come up with various solutions inspired by the disclosure of the present invention, and these solutions also belong to the disclosure scope of the present invention and fall within the protection scope of the present invention. Those skilled in the art should understand that the present invention specification and its drawings are illustrative and do not constitute a limitation on the claims. The scope of protection of the present invention is defined by the claims and their equivalents. The present invention specification contains multiple inventive concepts, such as "preferably" or "according to a preferred embodiment", which means that the corresponding paragraph discloses an independent concept, and the applicant reserves the right to file a divisional application based on each inventive concept. Throughout the text, the features guided by "preferably" are only an optional method and should not be understood as having to be set. Therefore, the applicant reserves the right to abandon or delete the relevant preferred features at any time.

Claims

1. A photodynamic therapy system for treating bladder cancer, characterized in that: It includes: A treatment catheter assembly (100) for performing operations of laser energy delivery and biosensor signal acquisition on a bladder lesion area; A central control unit (200) for performing data processing and generating control signals, The central control unit (200) is capable of obtaining tissue oxygen partial pressure and singlet oxygen concentration based on biosensor signals collected by the treatment catheter assembly (100), and thereby generating a control signal for regulating the laser energy delivery operation of the treatment catheter assembly (100), so that the treatment catheter assembly (100) can intermittently perform laser energy delivery operations on tumor tissue in the bladder lesion area, wherein the interval time length and the applied illumination parameters vary based on the real-time concentration change of the singlet oxygen, and the illumination parameters include light intensity and wavelength.

2. The system according to claim 1, wherein: The treatment catheter assembly (100) comprises: An irradiation module (110) is used to irradiate the bladder lesion area, and the emitted light includes therapeutic light and excitation light; A first monitoring module (120) is used to measure oxygen partial pressure distribution data of tumor tissue in the bladder lesion area in real time; The second monitoring module (130) is used to capture and quantify the spatial distribution of singlet oxygen during photodynamic therapy. The biosensor signals collected by the first monitoring module (120) and the second monitoring module (130) can be sent to the central control unit (200) for data processing to obtain tissue oxygen partial pressure and singlet oxygen concentration, thereby generating a control signal for regulating the interval time length and applied illumination parameters of the irradiation module (110).

3. The system according to claim 1 or 2, characterized in that The treatment catheter assembly (100) adopts a multi-layer composite structure design, and the multiple independent cavities configured therein include drug perfusion channels, so that when the photodynamic therapy system is activated, the treatment catheter assembly (100) can be introduced into the patient's bladder and positioned at the bladder lesion area, and then the bladder lesion area is perfused with a drug composition containing a photosensitizer through the drug perfusion channel.

4. The system according to any one of claims 1 to 3, characterized in that: During the initialization phase, the irradiation module (110) can output a detection beam according to preset parameters generated by the central control unit (200), so that the central control unit (200) can receive the oxygen partial pressure data of the tumor tissue in the bladder lesion area obtained by the first monitoring module (120), and then calculate the oxygen recovery time constant by the following formula: Where V t is the tumor volume; D eff is the effective diffusion coefficient; and These are respectively the highest oxygen partial pressure and the lowest oxygen partial pressure of the tumor tissue in the bladder lesion area obtained by the first monitoring module (120).

5. The system according to any one of claims 1 to 4, characterized in that: After entering the treatment phase, the central control unit (200) can generate a pulse width modulation signal based on a built-in adaptive intermittent control algorithm to drive the irradiation module (110) to perform adaptive intermittent irradiation on the bladder lesion area, wherein when the irradiation module (110) irradiates the bladder lesion area, the second monitoring module (130) can capture the phosphorescence signal and / or the fluorescence signal, and then send it to the central control unit (200) for data processing to obtain the singlet oxygen concentration.

6. The system according to any one of claims 1 to 5, characterized in that: The adaptive intermittent control algorithm built into the central control unit (200) includes the following pulse parameter dynamic equations: Where, T on and T off are respectively the start irradiation time and stop irradiation time of adaptive intermittent irradiation, 1 O2 is the singlet oxygen concentration.

7. The system according to any one of claims 1 to 6, characterized in that: The central control unit (200) performs a three-dimensional treatment response surface reconstruction every preset time to improve the treatment effect through the oxygen enhancement factor. Updated treatment effectiveness index for each region This enables the central control unit (200) to adjust the interval length and / or applied light parameters based on changes in the treatment efficacy index.

8. The system according to any one of claims 1 to 7, characterized in that: Oxygen enhancement factor built into the central control unit (200) and therapeutic efficacy index The calculation formula is as follows: Where, is the average oxygen partial pressure; E eff is the benchmark treatment efficacy index; is the intermittent time ratio correction term.

9. The system according to any one of claims 1 to 8, characterized in that: The central control unit (200) can calculate the oxygen enhancement factor based on real-time and therapeutic efficacy index Perform one or more of the following adjustments: When the therapeutic efficacy index Decrease, increase the laser intensity in that area proportionally to compensate for the loss of therapeutic effect; For areas where the oxygen enhancement factor is below a preset threshold, the proportion of therapeutic light is increased and the proportion of excitation light is reduced; Based on the reconstructed three-dimensional treatment response surface, the light spot residence time of tumor tissue with relatively higher treatment efficacy index in the bladder lesion area is extended, and the light spot residence time of tumor tissue with relatively lower treatment efficacy index is shortened.

10. The system according to any one of claims 1 to 9, characterized in that: When performing adjustments, the central control unit (200) can establish a dynamic adjustment mechanism for a safety threshold value that is dependent on oxygen partial pressure based on a preset safety constraint condition equation group, wherein the safety constraint condition equation group includes: In the formula, [ 1 O2] peak is the peak concentration of singlet oxygen monitored in real time during treatment; ΔT 黏膜 The temperature of the mucosal surface rises during treatment.

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