CN117503316A - A nanomedicine-mediated multi-physics coupled ablation device - Google Patents
A nanomedicine-mediated multi-physics coupled ablation device Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
- A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
- A61B2018/00577—Ablation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
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- Medical Informatics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Surgery (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
一种纳米药物介导多物理场耦合消融诊疗设备，属于消融诊疗一体化设备集成技术领域，包括WDM系统、管式多层结构多模态分子影像微探针和磁场，引入具有成像和消融双重功能的多物理场有：脉冲电场、磁场、超声波和激光，所述探针可实现在超声和光声影像技术下对病灶病理进行初步诊断，对治疗参数进行原位精细微调，指导现场介入激光辐照、超声波聚焦破碎和纳秒脉冲电场高压放电对病灶处肿瘤组织电极化消融技术，并对其进行串并联有机结合消融病灶，同时将纳米药物精准输送病灶部分，实现对病灶部分通过外加交变磁场对磁光纳米药物产生的热动力效应辅助作用促进肿瘤病灶处的消融增强和纳米药物的渗透，提高纳米药物介导的多场协同消融治疗效果。A nanomedicine-mediated multi-physical field coupling ablation diagnosis and treatment equipment, which belongs to the field of ablation diagnosis and treatment integrated equipment integration technology, including WDM system, tubular multi-layer structure multi-modal molecular imaging microprobe and magnetic field, introducing dual imaging and ablation capabilities The functional multi-physics fields include: pulsed electric field, magnetic field, ultrasound and laser. The probe can perform preliminary diagnosis of lesion pathology under ultrasound and photoacoustic imaging technology, perform in-situ fine-tuning of treatment parameters, and guide on-site interventional laser radiation. The electrolytic ablation technology of irradiation, ultrasonic focused fragmentation and nanosecond pulsed electric field high-voltage discharge is used to ablate the tumor tissue at the lesion, and the series and parallel organic combination is used to ablate the lesion. At the same time, the nanomedicine is accurately delivered to the lesion part to achieve the application of alternating current to the lesion part. The thermodynamic effect of magnetic fields on magneto-optical nanomedicines promotes ablation enhancement at tumor lesions and penetration of nanomedicines, improving the effect of nanomedicine-mediated multi-field collaborative ablation therapy.
Description
Technical Field
The invention relates to the technical field of nano-drugs and medical instruments, in particular to a tumor ablation instrument which is used for preparing and characterizing nano-drugs and is innovatively and jointly applied by combining multiple physical fields.
Background
According to the american cancer society 2021 statistics, there were estimated 1930 ten thousand new cancer cases and nearly 1000 ten thousand cancer deaths worldwide in 2020. As the largest metabolism and toxin expelling organ of human body, liver cancer is diagnosed in late stage, and the immunity, drug generation and apoptosis mechanism are unique, so that the development of specific drugs is difficult. The common molecular imaging and biochemical method is difficult to accurately detect in early stage, once a plurality of advanced stages are found, the development of safe and convenient high-efficiency liver cancer drugs with accurate image diagnosis and treatment is urgently needed.
In past developments, although traditional anticancer therapies: surgery, radiotherapy and chemotherapy have progressed therapeutically, but have caused great pain to patients due to problems of surgical injuries, postoperative infections, and the like. And the patient is required to visit the doctor in time, and the operation can achieve the optimal effect of operation excision under the condition that the malignancy degree of the tumor is low and no metastasis is found. Furthermore, due to the high penetrability of ionizing radiation in radiotherapy, normal cells beside a tumor in the human body are inevitably damaged. Thus, although radiation therapy is effective in killing tumor cells, it also damages normal cells of the patient. The physical condition declines. The chemotherapy drugs commonly used in clinic at present comprise doxorubicin, taxol, cisplatin and the like, and are widely applied to the treatment of cancers. However, abuse and overuse of drugs may cause adverse effects and chemotherapy drug resistance is common. As technology advances, many new therapeutic approaches have emerged, including physical field-based approaches, biochemical-based approaches, and these newly developed approaches have their own limitations. Such as biochemical-based methods, even for expensive CAR-T therapies that are effective against suspension/liquid cancer cells, are not capable against solid tumors; although targeted therapies can theoretically target cancer cells entirely, in practice, off-target situations exist due to the complexity of the biological microenvironment. For the method based on the physical field, the high-intensity focused ultrasound can activate T cell proliferation signal paths in the treatment process, improve T cell infiltration, regulate immune microenvironment, effectively improve anti-tumor effect and remote tumor growth inhibition effect, but can generate more heat to cause local pain and skin burn. The photothermal agent in photothermal therapy has excellent photothermal efficacy but is still refractory to biodegradability and potential toxicity, and near infrared light is not useful for tumors deep in tissues. Magnetic field therapy targets tumors through magnetic fields and locally non-invasively treats tumors, but the thermal effects of magnetic fields and electromagnetic radiation remain a potential threat to human health.
Nanosecond pulsed electric fields are considered as an emerging bioelectric technology and are very promising local therapies, showing great potential in cancer therapy. The nanosecond pulse electric field is used as high-power and low-energy electric pulse, and based on the pulse power physical principle, the target tumor is ablated by accumulating electric energy and releasing the electric energy in the form of nanosecond pulse. However, as the research is advanced, nanosecond pulsed electric fields have been found to have some drawbacks. Firstly, after nanosecond pulse electric field operation, part of tumor cells can escape, so that tumor recurrence and metastasis are caused, and secondly, normal cells can be damaged in the operation process. Nano-drugs have size-controllable, large mass ratios and unique physicochemical properties, and thus can be used at the molecular level for monitoring, control, diagnosis and treatment of biological systems, and tissue repair. The nanometer hybrid composed of noble metal and magnetic components is expected to be applied in wide fields including energy conversion, medical imaging and disease detection due to the unique physicochemical properties, high stability and excellent application prospect; however, the use of nanomedicines still has numerous unclear effects on human health and characteristics of various biological disorders that need to be overcome, including stability, surface modification and functionalization, multi-modal function, efficient drug delivery, and side effects; and the tumor cells cannot be completely eradicated by the simple nano-drugs.
Multiple physical field combination therapy is the dawn that later attacks cancer, and a combination of traditional and modern new therapies can help prolong patient life, overcome resistance and alleviate symptoms. Combination therapies for cancer treatment have shown that in different types of cancer, including liver cancer, the combination therapies using the device of the invention are more effective and can achieve higher overall survival rates than monotherapy. Therefore, the invention provides the cancer ablation instrument combining multiple physical fields with nano medicines on the basis of a domestic single physical field therapeutic instrument, and the ablation instrument has higher curative effect on multiple field coupling under the pulse strong magnetic field based on the research of the steady-state strong magnetic field in China at present. The instrument is a new direction in the field of tumor treatment and still in the research stage. Part of chemotherapeutic drugs and traditional drugs can be combined with multiple physical fields, and all show different synergistic effects, so that the treatment effect of tumors is improved.
Disclosure of Invention
The multi-physical field is used as a promising local tumor treatment technology based on a single physical field, the modern physical technology mediated multi-mode intelligent nano-drug is integrated into the multi-physical field (pulse electric field, magnetic field, ultrasonic wave and laser) treatment, and a novel combined treatment ablation instrument is designed.
A nano-drug mediated multi-physical field coupling ablation instrument mainly comprises the following parts: a multimode signal generating end and a WDM system (10) (the internal structure of the system is a common structure in the market), a multi-field coupling immune regulation and control drug-taking and imaging probe and a Maxwell Wei Dianci coil pair combination for providing a magnetic field;
the multimode signal generating end comprises a radio frequency signal generator (1), a nanosecond-femtosecond laser generator (2), a transient (microsecond-femtosecond) pulse high-energy electric field (3), a multimode fiber (7) and an ultrasonic generator (8); the system comprises a radio frequency wave band electromagnetic wave signal (4) generated by a radio frequency signal generator (1), a laser signal (5) generated by a nanosecond-femtosecond laser generator (2) and a transient pulse high-energy electric field (6) generated by a transient (microsecond-femtosecond) pulse high-energy electric field generator (3), wherein the transient pulse high-energy electric field is converged to a multimode optical fiber (7) through an optical fiber respectively, and the multimode optical fiber (7) is communicated with a WDM system (10); meanwhile, an ultrasonic generator (8) is arranged at the end part of the Wavelength Division Multiplexing (WDM) system (10) and positioned at the rear end port of the therapeutic catheter;
the WDM system (10) comprises two parallel single-mode optical fibers: a first single-mode optical fiber (20) and a second single-mode optical fiber (25); the main technology is WDM technology, its main principle is based on wavelength division multiplexing, a plurality of signals are combined into a broadband optical signal by modulating lasers with different frequencies, the optical signal propagates through the same optical fiber, the optical signals with different wavelengths are separated by adopting a wavelength demultiplexer at a receiving end, and the wavelength demultiplexer is a device for separating the optical signals with different wavelengths by utilizing the light splitting effect of a grating. The WDM system (10) has the main functions of separating detection signals, namely detection signals and treatment signals, namely optical signals (26) and treatment signals and optical signals (27) which are generated by regulating and controlling the nanosecond-femtosecond laser generator (2) and conducting the signals by using a second single-mode optical fiber (25) and a first single-mode optical fiber (20) respectively;
The multi-field coupling immune regulation and control drug-taking and imaging probe comprises a coupling treatment catheter and an ultrasonic imaging system coupled with the front end of the treatment catheter; the coupling treatment catheter is of a cavity structure and is divided into four sections along the shaft from the rear end to the front end: the first section, the second section, the third section and the fourth section are multi-field excitation ports (19), the first section, the second section and the third section of the inner surface of the coupling treatment catheter adopt integrated multi-physical field conduction layers (18), and the multi-physical field conduction layers (18) extend into the multi-field excitation ports (19) of the fourth section; the outer layers of the first section, the second section and the third section of the integrated multi-physical field conducting layer (18) are high-voltage insulating cavities (16) (can be annular cavities formed by insulating materials), and the high-voltage insulating cavities (16) are closely connected with the multi-field excitation ports (19); the outer layer of the third section high-voltage insulating cavity (16) is a high-voltage insulating layer (17); the outer layers of the high-voltage insulating cavities (16) corresponding to the first section and the second section are high-voltage output layers (14); the outer layer of the first section of high-voltage output layer (14) is an insulating woven layer (11), and the outer layer of the second section of high-voltage output layer (14) is a ten-thousand-volt nanosecond pulse reduction port (15) layer; the WDM system (10) is mainly positioned at the rear end of the coupling treatment catheter, and simultaneously, the first single-mode optical fiber (20) and the second single-mode optical fiber (25) of the WDM system (10) are parallel and axially penetrate through the cavity of the coupling treatment catheter; the cavity of the treatment catheter is also provided with a medicine inlet cavity (12), the first section of the rear end of the coupling treatment catheter is provided with a medicine inlet of the medicine inlet cavity (12), the side part of the fourth section is provided with a medicine outlet of the medicine inlet cavity (12), meanwhile, the cavity of the coupling treatment catheter is also internally provided with an ultrasonic detection film (13), the ultrasonic detection film (13) is tightly attached to the medicine inlet cavity (12), and the ultrasonic detection film (13) can receive an ultrasonic signal (9) generated by an ultrasonic generator (8);
An ultrasonic imaging system component is arranged at the front end of the fourth section, an ultrasonic shielding layer (30) perpendicular to the axial direction of the treatment catheter is arranged at the front end of the fourth section, the first single-mode optical fiber (20) and the second single-mode optical fiber (25) vertically penetrate through the ultrasonic shielding layer (30), a reflecting mirror (31) is arranged at the end part of the second single-mode optical fiber (25), the reflecting mirror (31) is connected with a photoacoustic transducer (32) through an optical path, and the photoacoustic transducer (32) can convert a detection signal-optical signal (26) into an acoustic signal (33) and send out ultrasonic waves (34) so that the ultrasonic waves (34) act on a focus part to send back scattered ultrasonic waves (35); an ultrasonic imaging system component (21) is arranged at the rear end of the ultrasonic shielding layer (30) and can obtain specific focus information according to the imaging of the back scattering ultrasonic waves (35);
further ultrasonic imaging system components include a backward scattering ultrasonic wave (35) signal receiver, pi-FBG (29) and a third single-mode optical fiber (24), wherein the third single-mode optical fiber (24) is positioned in the cavity of the coupling treatment catheter while one end passes through the ultrasonic shielding layer (30), the pi-FBG (29) is arranged on the third single-mode optical fiber (24) after the ultrasonic shielding layer (30) of the coupling treatment catheter, and the third single-mode optical fiber (24) is connected with an analysis imaging system and the like for complete ultrasonic imaging.
The front part of the multi-field coupling immune regulation and control drug-taking and imaging probe is covered with an alloy catheter (28), so that a reflector (31), a photoacoustic transducer (32), ultrasonic imaging system components and the like are positioned in the alloy catheter (28), and the end part of the first single-mode optical fiber (20) extends out of the alloy catheter (28);
the whole multi-field coupling immune control drug-taking and imaging probe, the second single-mode optical fiber (25) inside, the first single-mode optical fiber (20) and the like are collectively called a probe.
The Maxwell Wei Dianci coil pair combination (22) for providing the magnetic field is positioned around the focus viscera or part, symmetrically distributed and used for applying the magnetic field to the focus viscera or part. The Max Wei Dianci coil pairs are combined into a plurality of groups (6, 8, 12, etc.), thousands of turns of enameled wires are wound, alternating currents with different voltages are supplied, and then an alternating magnetic field of tens to hundreds of millitesla can be generated, so that therapeutic apparatuses with different sizes and shapes can be manufactured to adapt to different focus positions.
The drug delivered in the drug-entering cavity (12) is an anti-tumor drug which has magnetism and contains Rg 3.
The invention relates to a working method of a nano-drug mediated multi-physical field coupling ablation instrument, which is characterized in that the multi-physical field comprises a pulse electric field, a magnetic field, ultrasonic waves and laser, and comprises the following steps:
Firstly, a radio frequency signal generator (1) (for example, an AnaPico radio frequency generator, 9kHz to 40GHz,200 ns), a nanosecond-femtosecond laser generator (2) (for example, a GLPN laser 1.5ns, 10-100W) and a transient (microsecond-femtosecond) pulsed high-energy electric field generator (3) (for example, FPG 500-N, output voltage 500KV, pulse width 1-100 ns) respectively generate a radio frequency wave electromagnetic wave signal (4), an optical signal (5) and a transient pulsed high-energy electric field (6), the radio frequency wave electromagnetic wave signal (4), the optical signal (5) and the transient pulsed high-energy electric field (6) are respectively transmitted and summarized to a multimode optical fiber (7) through a single mode optical fiber (for simultaneous transmission of a plurality of signals), the multimode optical fiber (7) is directly connected with a WDM system (10), then the radio frequency wave electromagnetic wave signal (4) is transmitted to a multi-field excitation port (19) through a multi-physical field conducting layer (18), when a probe is inserted into a focus (23), the focus is directly acted on, the high-energy pulsed high-energy electric field is released by the multi-field excitation port (19), the transient high-energy electromagnetic wave signal is enabled to absorb heat energy signals through transient high-frequency or high-energy pulsed electric fields, and the abnormal electric field can absorb heat energy signals generated by the transient high-energy electric field and the transient high-energy electric field through the focus tissue, and the abnormal electric field can absorb abnormal tissue; or the photoelectric effect of high-frequency electromagnetic waves or the electromagnetic polarization effect of electromagnetic wave substances on the tissue or cells at the focus to destroy the normal functions of the cells and promote the death of the cells;
An optical signal (5) generated by the nanosecond-femtosecond laser generator (2) enters the WDM system (10) through a multimode optical fiber (7), is transmitted to a multi-field coupling immune regulation and control drug-taking and imaging probe, and is finally inserted into a focus for treatment and imaging through the probe;
imaging as further described above: wherein a part of the optical signals (5) are led into detection signals-optical signals (26) through a second single-mode optical fiber (25), reflected by a reflecting mirror (31) and transmitted to a photoacoustic transducer (32), the photoacoustic transducer (32) enables the detection signals-optical signals (26) to be converted into acoustic signals (33) and emit ultrasonic waves (34), when the ultrasonic waves (34) propagate to a focus part (23) in tissue, a part of the ultrasonic waves are scattered back by scatterers in the tissue to form backward scattering ultrasonic waves (35), the backward scattering ultrasonic waves (35) contain information about the focus, information about the position, shape, size, tissue properties and the like of a lesion can be provided, and the backward scattering ultrasonic waves (35) reversely propagate ultrasonic signals are subjected to ultrasonic imaging through an ultrasonic imaging system component (21) and an analysis imaging system;
still further, the backscattered ultrasound waves (35) complete the process of ultrasound rendering via the ultrasound imaging system component (21): the signal of the backscattered ultrasound (35) is received by a receiver and converted into an electrical signal, forming an echo signal (36), the echo signal (36) containing information about the lesion, such as position, shape, size, tissue properties, etc., is conducted via the pi-FBG (29) on the third single mode fiber (24) and the third single mode fiber (24), and by processing and analyzing the echo signal, an ultrasound image can be formed and used for medical diagnosis and lesion assessment. The echo signal (36) at this time may be external to the ultrasound imaging system: in ultrasound imaging, echo signals are returned by ultrasound waves reflected or scattered in tissue. Ultrasound imaging systems typically include an ultrasound transmitter that transmits ultrasound waves and a receiver that receives and processes echo signals. These devices enable the transmitter and receiver to communicate with each other and generate images via a cable or wireless connection.
Further treatment as described above: the other part of the optical signals (5) conduct incident therapeutic signals-optical signals (27) through the first single-mode optical fiber (20), the probe directly acts on the focus part when inserted into the focus part (23), and the front end part of the first single-mode optical fiber (20) releases high-energy laser beams, so that cell damage and necrosis can be caused, and the growth and diffusion of tumors are inhibited;
the signal of the transient impulse high-energy electric field (6) generated by the impulse high-energy electric field generator (3) is transmitted to the multi-field excitation port (19) through the high-voltage output layer (14) and directly acts on the focus part to generate a nanosecond impulse electric field acting on the lesion tissue, so that the permeability of tumor cells at the focus part can be changed, the permeation of nano medicines is facilitated, and the treatment effect is greatly improved. The multi-field excitation port (19) generates electricity (equivalent to a capacitor anode) after receiving pulse signals and inserting the pulse signals into a focus, a part of the electricity directly acts on the focus to play a role in treatment, and the rest of the electricity is transmitted to the high-voltage output layer (14) (equivalent to a capacitor cathode) through the high-voltage insulation cavity (16) (equivalent to a capacitor medium in the capacitor) through the multi-physical field transmission layer (18) to form a loop, so that the electricity utilization safety in the probe is ensured.
Under the excitation of an ultrasonic generator (8), an ultrasonic signal (9) can directly act on an imaging component in an external ultrasonic imaging system when in focus through an ultrasonic detection film (13) to realize acoustic imaging positioning of tumor tissues, can also directly act on a focus part through a multi-physical field conducting layer (18) to be transmitted to a multi-field excitation port (19) so as to generate a focused ultrasonic field acting on the focus part, can also change the permeability of tumor cells at the focus part, is beneficial to permeation of nano medicines, and greatly improves the treatment effect.
The stored magnetic nano-drug is delivered into lesion tissues through the drug-entering cavity (12), on one hand, the lesion sites are treated, and on the other hand, the magnetic nano-drug (such as the multi-mode clinical nano-drug (202110360364.0)) can be used as a contrast agent for MRI and CT imaging, and the nano-drug is tracked in three-dimensional depth in tissues or opaque organisms, so that the functions of organism cells are visualized. The Max Wei Dianci coil pair is arranged around a focus part or focus viscera in a combined way, and is electrified, so that the permeability of tumor cells at the focus part can be changed, the permeation of nano-drugs is facilitated, and the treatment effect is greatly improved; meanwhile, better movement and distribution of the magnetic nano-drug can be guided by different combined positions of the Maxwell Wei Dianci coil pairs.
The specific sequence of providing the pulsed electric field, the magnetic field, the ultrasonic wave and the laser (comprising which field is adopted), and the delivery sequence time of the medicine can be adjusted according to the needs.
The instrument adopts an ultrasonic echo sensing element and a tunable laser to design an intervention laser ultrasonic method which is low in cost, miniaturized, compatible and applicable with a nanosecond pulse tumor ablation treatment probe, is hopeful to break through the limit, realizes multi-mode image target focus puncture needle-in path visualization and tumor boundary real-time monitoring, and has quantifiable, controllable and predictable power assisting accurate ablation tumor treatment modes. The instrument can realize photoacoustic imaging, and can carry out depth imaging on tissues through ultrasonic waves, so that the definition and resolution of images are improved, and tumor positioning is more accurately carried out.
Magnetic nanomedicines, preferably multimode nanomedicines (202110360364.0), are a class of magnetic nanoparticles that play an important role in tumor therapy and imaging. Based on the above, the ultrasonic generating system, the nanosecond pulse electric field and the multimode image probe assist the multimode nano-drug to precisely intervene in the focus part, and then the movement and distribution of the multimode nano-drug in the body are controlled through the externally applied magnetic field. The magnetic field guides the multimode nano-drug through the magnetically permeable material or the magnetic nano-particles, so that the multimode nano-drug moves towards the tumor part and is accurately positioned to the tumor tissue. The directional delivery can greatly improve the concentration of the medicine in the tumor area and enhance the treatment effect. In addition, the magnetic field can also enhance the curative effect of the multimode nano-drug through the thermal therapy effect. The magnetic nanoparticles can generate heat under the action of a magnetic field, thereby inducing a local thermal therapy effect. The thermotherapy effect can promote release and permeation of the medicine, improve blood supply of tumor tissue, and enhance cell uptake and drug effect of the medicine.
The ablation instrument can kill tumor cells in large dose by performing multi-physical field effect, solves the dilemma that the tumor cells cannot be eradicated by a single nano-drug, and then part of tumor cells escape although the nano-drug is given at the moment, the nano-drug can rapidly target the corresponding part such as the liver, the nano-drug can specifically identify and kill the escaped tumor cells due to higher H2O2 concentration of the tumor cells, rg3 in the nano-drug can effectively promote and protect liver and kidney functions, and normal cells damaged by a single physical field are protected and repaired. Besides the obvious synergistic effect, the nanosecond pulse electric field with multiple physical fields can generate reversible electroporation on the cell surface, more nano-drugs can enter tumor cells through ultrasonic assistance, and the implanted nano-particles can be activated to release the drugs by using optical fibers and electromagnetic fields, so that the obvious synergistic effect is further achieved.
The subsequent application example proves that after the Au@CoFe-Rg3 nano-drug is combined with a plurality of physical fields, the inhibition effect of the Au@CoFe-Rg3 nano-drug on liver cancer cells is improved by 3.14 times compared with that of single nanosecond pulse. In addition, in the in-situ mouse liver cancer experiment, two models of early stage and late stage are designed for more vivid simulation of clinical results. Early model shows that the combined ablation instrument kills tumor cells in large dose through nanosecond pulse electric field and ultrasonic wave, and solves the dilemma that nano medicine can not eradicate tumor cells. After that, part of tumor cells migrate and escape, and the system can rapidly target the liver by using the Au@CoFe-Rg3 nano-drug under the action of optical fibers and a magnetic field, and specifically identify and kill the escaped tumor cells. In addition, rg3 in the Au@CoFe-Rg3 nano medicine can effectively improve and protect liver and kidney functions and protect and repair normal liver cells. Solves the problems of transfer recurrence and damage to normal liver cells in clinical application of multiple physical fields. The advanced model combined therapy can thoroughly solve the situations of tumor metastasis and recurrence after multiple physical field operations, can also protect normal cells, remarkably inhibit tumor growth on the basis of effectively inhibiting tumor metastasis, and remarkably improve the survival state and survival time of mice. The result shows that the combined ablation instrument can obviously inhibit the growth of tumors and improve the survival state and survival rate of mice. The research provides important theoretical significance and practical value for the research of novel combined anticancer instruments.
According to the application of the invention, the concentration of Au@CoFe-Rg3 in the nano-medicament is 1-5000 mug/mL, the electric field intensity of nanosecond pulse is 10-40kV/cm, the pulse width is 100-500ns, the electric shock times are 5-500 times, the magnetic field intensity is 0.001-10T, the diameter size of the optical fiber probe is 0.1-1.0mm, the size of the multimode nano-medicament delivery channel (diameter of the medicament inlet cavity) is 0.05-0.2mm, and the size of the ultrasonic detection film is 1.0-2.0mm.
The multi-physical field and nano-drug coupling ablation instrument provided by the invention complements the advantages of the two methods, takes in-situ liver cancer as a pathological model, and researches the biological mechanism and the synergistic mechanism of the combined therapeutic instrument on the action of liver cancer cells through in-vitro experiments and in-vivo animal anticancer curative effect experiments. The invention provides necessary experiment and theoretical guidance for the design of clinical application schemes, originally develops a novel therapy for precisely ablating liver cancer by combining multiple physical fields with nano-drugs, combines interaction among ablative instruments and research on apoptosis mechanisms of tumor cells, and can provide theoretical basis and clinical guidance for finding a novel method and a novel means for tumor treatment. Has important theoretical significance and practical value for realizing the autonomous innovation of anticancer therapy, new medicine and the upgrading and updating of corresponding domestic medical equipment in China and exceeding the international advanced level.
Drawings
FIG. 1 is a schematic diagram of an experimental device of a multi-physical-field ablation instrument used for experiments; (a) is an overall schematic; (b) Schematic diagram of the end of a multi-field coupling immune regulation drug-taking and imaging probe;
1. radio frequency signal generator 2 nanosecond-femtosecond laser generator 3 transient (microsecond-femtosecond) pulsed high energy electric field 4 radio frequency band electromagnetic wave signal 5 laser signal 6 transient pulsed high energy electric field 7 multimode fiber 8 ultrasonic wave generator 9 ultrasonic wave signal 10 wdm system 11 insulating braid 12 cavity 13 ultrasonic probe film 14 high voltage output layer 15 tens of kilovolt nanosecond pulse reduction port 16 high voltage insulating cavity 17 high voltage insulating layer 18 multiple physical field conducting layer 19 multiple field excitation port 20 optical fiber 21 ultrasonic imaging system component 22 maxwell Wei Dianci coil pair combination 23 focus 24 third single mode optical fiber 25 second single mode optical fiber 20 first single mode optical fiber 26 probe signal optical signal 27 therapeutic signal optical signal 28 alloy conduit 29 pi-FBG 30 ultrasonic wave shield 31 mirror 32 ultrasonic wave transducer 33 acoustic signal 34 ultrasonic wave 35 backscattering ultrasonic wave 36 echo signal.
FIG. 2 shows the in vitro MRI imaging effects of Au@CoFe NPs (a) and Au@CoFe-Rg3 (b), wherein the relationship between the relaxation time and the relaxation rate of T2 is that the relaxation time is shorter as the relaxation rate is higher under different drug concentrations, so that the nano-drug is well aggregated at a focus part, the nano-drug T2 is imaged above a curve in a weighting way, and the Au@CoFe-Rg3 is shorter and better aggregated at the focus part under the same concentration; (c) The MRI imaging effect in the Au@CoFe-Rg3 body is uniformly distributed on the tumor part along with the time; (d) Quantitative analysis of MRI imaging effects in Au@CoFe-Rg 3.
FIG. 3 (a) CT imaging effect of Au@CoFe-Rg3 in vitro; (b) CT imaging effect in Au@CoFe-Rg 3; (c) Quantitative analysis of CT imaging effect in Au@CoFe-Rg 3.
FIG. 4 (a) cytotoxicity of Rg3, au@CoFe NPs and Au@CoFe-Rg3 on hepatoma cells; (b) Quantitative analysis of Annexin V-FITC/PI apoptosis detection after 24 hours of treatment with different drugs; (c) Flow cytometry was performed on liver cancer cells after 24 hours of treatment with different drugs, and Annexin V-FITC/PI apoptosis assay was performed. Figure 5. Effects of different time additions of drugs on combination therapy cytotoxicity, nanodrugs were added before, after and four hours after the multi-physical field effect, respectively, to determine the optimal combination time.
Fig. 6. Early model nanosecond pulse experiments were performed with digital imaging before, during and after the execution of the experiment.
FIG. 7. (a) digital imaging of isolated tumors in vitro following different groups of treatment in early models; (b) Early model different treatment groups treated mice for weight changes; (c) Early model survival curves for tumor-bearing mice of different treatment groups.
Fig. 8. H & E staining analysis of liver and tumor tissue of different groups of early models.
Fig. 9. Early model analysis with blood biochemical tests of mice after different treatments.
Fig. 10. Digital imaging of late model multiple physical field experiments before, during and after the execution.
Figure 11, (a) digital imaging of isolated tumors in vitro following different groups of advanced model treatments; (b) Advanced model weight changes in mice were treated in different treatment groups; (c) Advanced model survival curves for tumor-bearing mice of different treatment groups.
Fig. 12H & E staining analysis of different groups of liver and tumor tissues in the late model.
Fig. 13 analysis of H & E staining of major organs of mice after different treatments in late model.
Detailed Description
The invention will be further illustrated with reference to specific examples. These examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
Under the positioning of focus through preliminary CT, MRI and ultrasound, the precise introduction of multiple physical fields with imaging and ablation dual functions is as follows: the multi-mode molecular image microprobe with a tubular multi-layer structure is an important component part for pulse electric field ablation, has the advantages of performing preliminary diagnosis and qualitative on focus pathology under ultrasonic and photoacoustic imaging technologies, performing in-situ fine tuning on treatment parameters, guiding the on-site use of the multi-mode molecular image microprobe with a tubular multi-layer structure to intervene in laser irradiation, ultrasonic focusing breaking and nanosecond pulse electric field high-voltage discharge to electrically polarize tumor tissues at a focus, performing series-parallel organic combination on the multi-mode molecular image microprobe to ablate the focus, simultaneously accurately conveying nano medicaments to the focus part, and promoting ablation enhancement and nano medicament penetration at the focus part through the auxiliary effect of an external alternating magnetic field on a thermo-dynamic effect generated by magneto-optical nano medicaments, thereby further improving the multi-field synergistic ablation treatment effect mediated by the nano medicaments.
The schematic structural diagram of the nano-drug-mediated multi-physical-field coupling ablation instrument adopted by the embodiment of the invention is shown in (a) and (b) of fig. 1.
The insulating braid 11 is typically made of glass fiber, polyester fiber, polyimide fiber, or polymer material, etc., and is mainly used to protect the circuits and transmission components inside the probe from external interference and damage. The drug-feeding cavity 12 is made of polymer plastics, stainless steel alloy or borosilicate glass material according to the application of drugs. The cavity is centrally located in the probe for storing the medication required for treatment and delivering the medication into the diseased tissue. The ultrasonic detection film 13 can adopt polyimide, polyetherimide, polymethyl methacrylate or polystyrene and other materials, and realize acoustic imaging positioning of tumor tissues by utilizing cavitation phenomenon formed by ultrasonic waves in human bodies. The high voltage output layer 14 may be made of aluminum alloy, steel-cored aluminum stranded wire, copper, or high strength composite material. This layer is primarily used to output high voltage electrical energy to the multi-field excitation port 19 of the probe to generate nanosecond pulsed fields, radio frequency fields and focused ultrasound fields that act on the diseased tissue. The tens of thousands of volts nanosecond pulse reduction port 15. A metal alloy material may be used. The port is mainly used for forming a nanosecond pulse electric field loop with the multi-field excitation port so as to generate a high-strength nanosecond pulse field to ablate and treat pathological tissues. The high voltage insulating chamber 16 may be made of polyethylene, polyimide, polytetrafluoroethylene, fiberglass, or ceramic. The cavity is mainly used for insulating a high-voltage circuit inside the probe so as to ensure the safety and reliability of the circuit. The high-voltage insulating layer 17 can be made of polyethylene, polyimide, polytetrafluoroethylene, glass fiber or ceramic and the like, and is mainly used for isolating an external electric field loop of a ten-thousand-volt nanosecond pulse reduction port and a multi-field excitation port so as to prevent the structural damage of a pulse electric field. The multi-physical field conductive layer 18 may be made of aluminum alloy, steel-cored aluminum strands, copper, or high strength composite materials. The layer is mainly used for transmitting various physical fields of external input, such as a radio frequency field, a nanosecond pulse field, a high-focusing sound field and the like. The multiple field excitation ports 19 may be formed of a metal alloy material. The port is mainly used for outputting various physical fields to pathological tissues so as to realize accurate interventional therapy. The first single-mode optical fiber 20 can be made of quartz glass, borosilicate glass, fluoride glass, copper-cadmium-selenium crystal, optical plastic and the like, and the optical fiber integrates infrared, fluorescence and surface plasma. The second single-mode optical fiber 24 can be made of quartz glass, borosilicate glass, fluoride glass, copper-cadmium-selenium crystal, optical plastic and other materials, and the optical fiber integrates infrared, fluorescence and surface plasma. Single mode optical fiber 25, supra. Single mode optical fibers 20, supra. The probe signal-optical signal 26 (a few hertz-a few tens hertz), the therapeutic signal-optical signal 27 (a few hundred hertz), the alloy conduit 28, which may be made of stainless steel, titanium alloy, siliconized glass, polycarbonate, etc., may be precisely positioned within the tumor tissue, pi-fbg 29, a typical non-uniform periodic fiber grating, by introducing a phase shift into a specific region of the grating region of the fiber bragg grating, thereby opening a transmission window with a very narrow bandwidth in its reflection spectrum stop band. The unique spectral characteristics lead the ultrasonic imaging device to have good application prospect in the sensing of dynamic signals such as ultrasonic detection and the like, and the ultrasonic imaging device is used for collecting back scattering ultrasonic waves from focus positions. The ultrasound shield 30 prevents or reduces the propagation and penetration capabilities of ultrasound waves within the catheter to reduce its impact on tumor imaging. The mirror 31 changes the direction of the incident light signal without changing the wavelength and frequency of the light. Photoacoustic transducer 32 is a device for photoacoustic imaging and photoacoustic therapy that functions to convert light energy into acoustic wave energy or convert acoustic wave energy into light energy. The back-scattered ultrasonic wave 35 is a back-propagated ultrasonic signal formed by scattering of a portion of the ultrasonic wave back by scatterers in the tissue as the ultrasonic wave propagates to the focal site within the tissue. The back-propagated ultrasonic signals of echo signals 36 are received by a receiver and converted to electrical signals to form echo signals. See fig. 1 (b).
Example 1
The unique magnetic properties of Au@CoFe NPs and Au@CoFe-Rg3 are considered to be used as contrast agents for MRI and CT imaging. Molecular imaging is suitable for diagnosis of various diseases due to the advantages of noninvasive property, high spatial resolution and tissue sensitivity, so that visualization of organism cell functions is possible. In molecular imaging techniques, MRI is used to morphologically and functionally image the anatomy and physiological processes of the body. Based on relaxation and biocompatibility during imaging, suitable MRI contrast agents are required to achieve high specificity. The T2 weighted spin echo imaging effect and corresponding T2 relaxation rates of the effective metals (Co and Fe) concentration dependence in Au@CoFe NPs and Au@CoFe-Rg3 are shown in FIGS. 2 a-b. Their T2 relaxation and concentration show perfect linear relationship, and the linear coefficients of Au@CoFe NPs and Au@CoFe-Rg3 are respectively 0.978 and 0.998. And MRI imaging of living animals is carried out, as shown in fig. 2 c, the T2 value of Au@CoFe-Rg3 in the liver is smaller and smaller along with the change of time, and the Au@CoFe-Rg3 is enriched in the liver in a targeting way, so that an uneven additional magnetic field is formed, the transverse magnetization phase of protons is changed when water molecules pass through the uneven magnetic field, the disappearance of the transverse magnetization phase is accelerated, and the T2 relaxation process is obviously shortened, so that the image darkens. Furthermore, the combination of MRI and CT may enable a highly accurate diagnosis of the disease. FIG. 3 shows CT signal intensities of Au@CoFe-Rg3 at different concentrations, indicating that good linear relationship is exhibited as the concentration of the drug increases; in addition, animal in-vivo experiments are carried out, which show that due to excellent absorption of Au to X rays, after intravenous injection of medicines, along with Au@CoFe-Rg3 targeting liver, the change of CT signals of the liver along with time is found to be obviously stronger. These results all indicate that au@cofe-Rg3 is a multimode clinical nanomedicine that allows MRI and CT imaging and three-dimensional depth tracking of the nanomedicine with enhanced resolution within tissues or opaque organisms.
Example 2
The toxicity and mechanism of Au@CoFe-Rg3 nano medicine on liver cancer cells are studied in vitro. The hepatocellular carcinoma cell line LM3 was incubated with Au@CoFe, au@CoFe-Rg3 nanomaterials and Rg3 for 24 hours. The results show that the Au@CoFe and Au@CoFe-Rg3 nano-drugs show obvious cytotoxicity to tumor cells under the concentration gradient (0.001 mug/ml-20 mg/ml). In addition, compared with pure Rg3 and Au@CoFeNPs, the Au@CoFe-Rg3 nano-medicament with the same concentration shows obvious superiority, has excellent inhibition effect on liver cancer cells, and further verifies the synergistic effect of the Au@CoFe-Rg3 nano-medicament (a in fig. 4). The effect of different drugs on tumor apoptosis was also confirmed using a typical annexin V-FITC/PI apoptosis assay. All drugs kill tumor cells through apoptosis, rg3 mainly through late apoptosis, while Au@CoFe NPs and Au@CoFe-Rg3 nano-drugs have early and late apoptosis. In addition, a higher level of apoptosis (44.69%) was detected in LM3 cells treated with au@cofe-Rg3 nanomedicine compared to cells treated with Rg3 and au@cofe NPs alone. The results confirm that apoptosis after incubation of Au@CoFe-Rg3 nanomedicine is caused by activation of apoptosis (b-c in FIG. 4).
Example 3
The anti-tumor curative effect of the multi-physical field (pulsed electric field, magnetic field, ultrasonic wave and laser) combined nano-drug is explored, cytotoxicity research is firstly carried out, and parameters of a high-energy transient pulsed electric field are fixed: pulse width, 0.1ps-100ms, voltage gradient: 10V/cm-1X 10 7 V/cm, frequency: 0.2-1×10 3 Hz; multipole rotating magnetic field: the parameters are that the magnetic field intensity is 0.01 mu T-20T, and the frequency is 0.01-1 multiplied by 10 4 Hz; ultrasonic assistance: the parameters are the frequency of 0.2-1×10 6 Hz, power of 10 mu W-300W, energy density of 0.1-3W/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the High-energy transient pulse laser parameters: pulse width of 0.1fs-100ns, single pulse power of 1 mu W-10W, frequency of 0.2-100MHz, and output energy of 100-1×10 5 J. Nano-drug (au@co of examples 1 and 2Cytotoxicity experiments are carried out with the concentration of Fe-Rg3 of 200 mug/ml (IC 50 concentration), and in order to understand the anti-tumor efficacy and mechanism of the multi-physical field combined multimode nano-drug in depth, the Fe-Rg3 is respectively before the multi-physical field acts, and after the multi-physical field acts (the specific parameters are respectively 100ns,2.5x10 of high-energy transient pulse electric field parameters 4 V/cm,3Hz; multipole rotating magnetic field parameter 1 mM, 50Hz; ultrasound auxiliary field parameters 0.85MHz,200W,1W/cm 2 The method comprises the steps of carrying out a first treatment on the surface of the The high-energy transient pulse laser parameters are 100ns,300mW,0.2MHz and 1800J. ) Nano-drugs were added four hours later to determine the optimal combined action time. As shown in figure 5, the effect of adding nano-drugs before the ablation of multiple physical fields is unstable, and the high-voltage nanosecond pulse can affect the structure or performance of the nano-drugs (such as separation caused by conjugate coupling fracture of Rg3 and metal particles on the outer layer), so that the effect of the nano-drugs is affected, and the structure and performance of the nano-drugs are destroyed; and meanwhile, the effect of the multi-physical field ablation on cells is not single variable any more, and the combined effect of the nano-drug with the structure and composition changed and the multi-physical field is greatly reduced. The effect of adding nano-drugs after the multi-physical field ablation is obvious, because reversible electroporation of cells occurs after the multi-physical field ablation, and the nano-drugs can enter the cells conveniently under the activation of ultrasonic assistance and multipolar rotating magnetic fields, so that the nano-drugs can enter the cells in a large amount to play a role on the premise of not affecting the structure and the performance, and the high-efficiency synergistic treatment effect can be played by combining the multi-physical field ablation; after the multi-physical field ablation for four hours, cells begin to adhere, at the moment, most of the cells are subjected to reversible electroporation on the cell surface, the cell membranes tend to be complete, and the cell internalization efficiency of the nano-drug is reduced, so that the effect is not as obvious as that of immediately administering the nano-drug after the multi-physical field effect. The relative cell viability of fig. 5 shows that the effect of administration immediately after the multiphysics is the best among the various effects. And according to the nanosecond pulse shock times in the multiple physical fields, the influence of the nanosecond pulse before less than 25 times on the cells is less, when the nanosecond pulse shock times are more than 25 times, a remarkable slope change appears, which indicates that the shock times about 25 times are possibly a critical value, and when the shock times are less than 25 times, the influence of the nanosecond pulse on the cells is less, when the shock times are less than 25 times, the influence of the nanosecond pulse on the cells is less Nanosecond pulses exert a remarkable effect gradually when the number of pulses is greater than 25, but it is found that the survival rate of cells decreases less after the number of pulses is greater than 50, and the effect does not change remarkably when the number of electric shocks is increased, and the effect of the electric shocks becomes smaller because the rest of cells possibly generate resistance to the electric shocks, and the above results show that the number of electric shocks is the optimal parameter for the cell experiment for 25-50 times.
Example 4
The method has the advantages that the anti-tumor curative effect of the combination of multiple physical fields (parameters are the same as those of the embodiment 3) of the living animals and the nano medicines (parameters are the same as those of the embodiment 3) is achieved, the living animal model of the in-situ liver cancer is established, the early-middle model and the late model are designed by combining the clinical situation, the model is closer to the clinical situation, and a road is opened for the subsequent clinical application. After the animals are adapted to the environment, the liver lobes are opened to take out the in-situ injection of the LM3 cells containing fluorescence, an early-medium stage model is formed after two weeks, the tumor generation condition is observed, and 21 days of nano-drug treatment is carried out after the fourth week of multi-physical field action. The nanosecond pulse experimental process is shown in fig. 6, which shows the operation process, the preoperative tumor tissue is bright and fresh, and along with the operation, the multi-physical field plays a role, so that the situation that the tumor part becomes dark and necrosis occurs is obviously found. In fig. 7 a, it is shown that after the treatment of the seventh week of the combination ablative apparatus, the liver and tumor pictures are obtained, and it is obviously found that, compared with the control group, the multiple physical fields and the combination treatment group effectively inhibit the generation of tumors, and the weight statistics can obviously see that the weight of the mice after the multiple physical fields operation is obviously reduced, because the multiple physical fields operation (the fourth week) has a certain effect on the physical state of the mice, but the effect of the multiple physical fields ablative operation on the mice can be reduced by using the combination treatment apparatus, the weight obviously starts to rise after one week of administration, and after two weeks of administration, the weight is already about to be about normal value, and after three weeks of administration, the weight is already about to be about equal to that of the control group, so that the effects of the nano-drug such as survival state improvement, liver and kidney function protection can be achieved on the basis of inhibiting the residual tumor cells of the multiple physical fields operation are verified (fig. 7 b). And the survival curve of the mice after nanosecond pulse is counted for a long time later, the final survival statistics of fig. 7c show that the mice of the control group have all died about 60 days due to uncontrolled growth of the tumor, and the multi-physical-field group has obvious killing effect on the tumor during operation, but cells transferred in the later stage also start to crazy generation and are not effectively controlled, and finally the mice of the nanosecond pulse group are all died about 80 days, and the service life of the mice of the control group is prolonged by 20 days relative to the mice of the control group. The combined ablative instrument treatment group kills a large number of tumor cells in an initial multiple physical fields, and part of escaped tumor cells are killed basically after the nano-drug is continuously administered for 21 days, so that the state of the mice can be improved, normal liver tissues are repaired, most of tumors in the mice are basically cured, and the result shows that the half mortality rate of the mice in the combined ablative instrument treatment group is improved by a matter which is higher than that of the mice in the control group and the multiple physical fields.
Example 5
H & E staining of liver and tumor tissue, as shown in FIG. 8, the control group liver has metastasized first, because the tumor is larger and uncontrolled, part of tumor cells metastasize to other nearby liver tissue through blood, and the obvious accumulation of tumor cells in the tumor site of the control group forms a closed tumor microenvironment; a small amount of metastasis of liver occurs in the group of multiple physical fields, and part of the metastasis effect of tumor cells is not killed in the operation process of the multiple physical fields (the parameters are the same as those of the embodiment 3.4); the tumor part has obvious apoptosis necrosis phenomenon but normal tissues beside the tumor are synchronously damaged; and the optimal combined ablative instrument treatment group finds that part of normal cells at the tumor part infiltrate, and proves that Rg3 contained in the nano-drug has an obvious protective effect on the liver. To assess the in vivo biosafety of the different treatment groups, toxicity evaluations were performed after experimental treatment. For the early-mid model, blood from mice was collected after the seventh week of sampling for blood biochemical analysis to assess in vivo toxicity. As shown in fig. 9, two liver function indexes are shown in the blood biochemical result graphs of mice of different groups in the early-middle stage model: the multi-physical field groups of alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) are obviously increased, because the multi-physical field operation produces a certain injury effect on the liver of the mice, slight liver injury is caused, and the combined ablation instrument treatment group inhibits the metastasis of the liver of tumor cells due to the effective liver and kidney protection function of Rg3, and the result is clearly compared with the single multi-physical field group, thereby proving the superiority of the combined ablation instrument. Three kidney function indicators: uric Acid (UA), urea nitrogen (BUN), and Lactate Dehydrogenase (LDH); three cardiac function indicators: creatinine (CERA), creatine Kinase (CK), creatine kinase isozymes (CK-MB) all showed normal, demonstrating that none of the groups caused significant renal and cardiotoxicity in vivo.
Example 6
A model of advanced liver cancer in situ (corresponding to a clinical advanced liver cancer patient) is established, and after the model is established for three weeks, a multi-physical field (the parameters are the same as those of the embodiment 3.4.5) experiment is started after the model is adapted to the environment. As shown in fig. 10, the tumor of the mice in the late model has a diameter of about 1cm, and the necrosis and apoptosis of the tumor part after the ablation of the multiple physical fields are more obvious to the naked eye compared with the early and middle model. Fig. 11a shows the liver and tumor pictures obtained after the experiment is completed, and the most excellent inhibition effect is obviously found compared with the control group and the multi-physical field group in combination with the ablation instrument treatment group. And the weight statistics fig. 11b also confirms that the multi-physical-field ablation combined nano-drug group obviously improves the living and living states of mice, solves the problem of weight reduction after multi-physical-field surgery, and the living curve graph 11c shows that the mice are all dead about 55 days due to uncontrolled growth of tumors in a control group, and obviously discovers that the living curve of the mice treated by the combined ablation instrument is superior to the living curves of the other two groups, and half mortality is about 70 days.
Example 7
H & E staining of liver and tumor tissue as shown in fig. 12, both control and multiphysics (parameters same as example 3.4.5.6) groups had metastasized due to the metastasis of some tumor cells to other liver tissue nearby via blood; the combined ablation instrument treatment group does not have any liver metastasis, the advantages of the combined ablation instrument are again proved, and meanwhile, the H & E of tumor tissues is found, as the tumor is relatively large during operation, the focus limit is easy to lock, and the influence of the multiple physical field groups on normal liver tissues is small. However, it is obvious that the inhibition effect of many physical fields on the late-stage tumor model is not as good as that of the early-stage tumor model and even has less obvious individual inhibition effect, and this directly proves the importance of the application of the designed multimode nano-drug in the imaging and early diagnosis directions for providing a diagnosis and treatment integrated platform for patients. The inhibition effect on the advanced tumor model is also obvious for the multi-physical field group, which shows that the multi-physical field and the nano-drug have obvious synergistic effect on the inhibition on the advanced tumor model, and the multi-physical field kills most cancer cells, so that electroporation is generated on the surface of the escaped residual tumor cells, and the nano-drug can enter the tumor cells conveniently through the ultrasonic assistance and the magnetic field activation, and meanwhile, due to the autonomous targeting of the liver of the nano-drug, the tumor cells which are dissociated after the ablation of the multi-physical field can be killed subsequently, and the metastasis of the liver or other organs of the tumor cells can be inhibited.
For the late model, safety tests were also performed, and pathology graph 13 of H & E sections of the main organs of mice of different groups showed that all groups did not cause macroscopic pathology damage to mice, confirming that the multiple physical fields and the combined ablative instrument treatment groups in the late model still had high biosafety in vivo. The results show that the combined ablation instrument therapy can kill part of escaped tumor cells after the multi-physical-field surgery, protect liver and kidney functions, improve the living and living state of mice, verify that no substantial organ damage occurs in the treatment process of the combined ablation instrument through H & E sections of main organs, and verify the safety of the combined treatment mode.
Example 8
The curative effect of combining multiple physical fields (pulsed electric field, magnetic field, ultrasonic wave and laser, and the parameters are the same as those of the embodiment 1.2.3.4.5.6.7) with the nano-medicament on pancreatic cancer is explored. First, image techniques such as MRI and CT are used to initially locate and measure pancreatic cancer tumors, so as to obtain information such as the size and position of a lesion. The probe is precisely guided to the focus of pancreatic cancer tumor by the ultrasonic auxiliary effect. The ultrasound technique can provide real-time image guidance to ensure accurate probe access to the lesion. Under the real-time guidance of ultrasonic images, a pulsed electric field is applied to ablate the focus. By observing the ultrasonic image, the ablation process can be monitored in real time and the accuracy of treatment is ensured. After the pulsed electric field treatment, the nano-drug is injected into the focus part through the probe. The nano-drug has the capability of targeting pancreatic cancer cells and can be selectively enriched in the pancreatic cancer cells. The ultrasound auxiliary effect can promote the penetration of nano-drugs to focus parts and the intracellular uptake of tumor. This is beneficial for the nano-drug to have a secondary killing effect on tumor cells which have not been completely destroyed before. After the nano-drug enters the focal site, a laser is used to irradiate the treatment area. Some components of the nano-drug may respond to laser energy, for example, absorb or scatter light energy, converting it into thermal energy. Thus, the laser can trigger a local thermal effect of the nano-drug, thereby destroying cancer cells or promoting drug release. Finally, the magnetocaloric effect is induced by the externally applied rotating magnetic field. The magnetic nano-drug can generate a magnetocaloric effect under the action of a magnetic field, namely, absorbs the energy of an external magnetic field and converts the energy into heat energy. Thus, the magnetocaloric effect may generate a local thermal effect within pancreatic cancer cells, thereby destroying the cancer cells or promoting drug release. Plays a key role in the subsequent tumor treatment. Can prevent the recurrence and metastasis of tumor, and finally achieve the aim of completely eliminating tumor cells. In the experimental process, a mouse in-situ pancreatic cancer model is selected and divided into: control group, nanometer drug treatment group, pulsed electric field treatment group, laser treatment group, ultrasonic treatment group, rotating magnetic field treatment group and multiple physical fields combined treatment group. The mice are cultured for 60 days after two weeks, and in the treatment process, the focus is positioned and monitored by using the MRI, CT and other imaging technologies, so that the treatment accuracy is ensured. After the treatment is finished, the pancreatic tissue of the animal is taken out, focal sections are prepared, and pathological analysis is performed. The effect of the treatment and the killing effect on tumor cells were evaluated by pathological observation and analysis.
Through these experimental procedures and animal experimental methods, we demonstrate the effectiveness and feasibility of multi-physical field treatment of pancreatic cancer tumors. The method combines a plurality of physical field technologies such as MRI and CT preliminary positioning, probe positioning under ultrasonic guidance, pulse electric field ablation under ultrasonic image guidance, nano-drug injection and permeation, photodynamic activated immunity, magnetomotive magnetocaloric therapy and the like, can kill tumor cells to the maximum extent, and can prevent tumor recurrence and metastasis.
Example 9
The lung cancer resisting effect of the combination of multiple physical fields (magnetic field, ultrasonic wave and laser, and the parameters are the same as those of the embodiment 1.2.3.4.5.6.7.8) and the nano medicine is explored. First, the lung cancer focus is initially positioned and measured by MRI and CT technology, and the size and position of the focus are determined. Then, the nano-drug is precisely injected to the focus of lung cancer by using an ultrasonic auxiliary technology through a probe so as to enhance the penetration of the nano-drug and the absorption in tumor cells. Has effect in killing tumor cells. After the nano medicine is injected into the focus, the focus part is irradiated by laser, and the heat effect is generated by using the energy of the laser, so that the tumor cells are directly destroyed or the release of the nano medicine is promoted, thereby achieving the aim of treatment. Finally, a rotating magnetic field is added to the focus part to induce a magnetocaloric effect so as to realize the local thermal effect of the magnetic nano-drug in lung cancer cells. Plays a key role in the subsequent tumor treatment. Can prevent the recurrence and metastasis of tumor, and finally achieve the aim of completely eliminating tumor cells.
In the experimental process, a mouse in-situ lung cancer model is selected firstly and divided into: control, laser, nanomedicine, magnetic field and combination treatment groups mice were incubated for two weeks and then started for 60 days. In the treatment process, the treatment effect of the tumor focus is monitored, including periodically detecting the size change of the focus by using imaging technologies such as MRI, CT and the like, performing cytopathology detection, recording indexes such as survival rate of animals and the like. And finally, analyzing and evaluating according to experimental results, and evaluating the curative effect and safety of the multi-physical-field treatment on lung cancer tumors. Through the experimental method and the animal experimental steps, the lung cancer tumor can be effectively treated, the recurrence and the metastasis can be prevented, and finally the aim of completely eliminating tumor cells can be achieved through the combined action of multiple physical fields, including ultrasound, laser and magnetic fields, and the local thermal effect of nano medicines.
Example 10
The anti-glioma curative effect of multiple physical fields (magnetic field, ultrasonic wave and pulsed electric field, and the parameters are the same as those of the embodiment 1.2.3.4.5.6.7.8.9) is explored. Firstly, imaging and scanning the brain of an animal by using imaging technologies such as MRI, CT and the like, obtaining the information such as the size, the position, the morphology and the like of a colloid tumor, and determining a treatment target area. Then, the animal is placed in a pulse electric field treatment device, and the frequency, amplitude, pulse width and other parameters of the current are changed to treat the colloid tumor. Finally, a continuously externally-applied rotating magnetic field is used for focusing the tumor cells on the colloid tumor area, so that local thermal effect is generated in the tumor cells, and the cancer cells are destroyed.
In the experimental process, a mouse in-situ glioma model is selected firstly and divided into: control, pulsed electric field, magnetic field, and combination treatment mice were incubated for two weeks and then started for 90 days. During the treatment process, the treatment effect can be monitored and evaluated through imaging technologies such as MRI, CT and the like. Indicators such as reduction degree, morphological change and the like of the colloid tumor, physiological conditions, behavior and the like of animals are observed to evaluate the effectiveness of treatment.
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