Cancer, also known as malignant tumor, is one of the major diseases that seriously endanger human health and life. According to the latest report on cancer in China by the internationally renowned cancer journal CA: A Cancer Journal for Clinicians, there were about 4.292 million new cancer cases and 2.814 million cancer deaths in China in 2015, accounting for new global deaths and deaths. 22% and 27% of cases. Cancer is becoming an important factor in harming public health security in China. Therefore, timely, efficient and accurate diagnosis and treatment of cancer is not only related to people’s life and health and quality of life, but also to the sustainable development of economy and society. Traditional methods of cancer treatment mainly include surgical resection, chemotherapy (chemotherapy) and radiation therapy (radiation). However, due to the difficulty in labeling the tumor tissue during the operation and the easy transfer of the original cancer cells, it is easy to relapse after surgery. Chemotherapy and radiotherapy also have significant killing effects on normal tissues, with large side effects, and tumor cells are easily tolerant to chemotherapy and radiotherapy. Therefore, the development of new and efficient tumor treatment methods has become a research hotspot.
In recent years, with the rapid development of nanotechnology, new methods for tumor treatment based on nanomedicine, including photodynamic therapy, photothermal therapy, and immunotherapy, have been continuously developed and studied. However, most of these treatments are still in basic research or The clinical trial phase is faced with a series of challenges and challenges. For example, the enhanced permeability and retention effect (EPR) of nanomedicine in solid tumors is one of the focuses of debate. The EPR effect refers to the phenomenon that some specific size macromolecules (such as liposomes, nanoparticles, and some macromolecular drugs) are more likely to penetrate into tumor tissues and remain in the long term (compared to normal tissues). At the beginning of its discovery, the EPR effect was once considered to be the achilles of cancer, enabling nanomedicine to be efficiently enriched in tumor sites, making tumor treatment possible. However, the latest research shows that the average tumor intake of nanomedicine is only 0.7% of the injected dose. In fact, the delivery of nanomedicine to tumor tissues and cells requires a complex and lengthy process. In this process, first, nanomedicine needs to avoid the body’s immune surveillance to prevent the capture of serum opsonin protein; secondly, nanomedicine needs to selectively exude in the tumor site, and overcome the infiltration of cancer cells, through the surrounding tissue of the tumor, Avoid macrophage uptake, overcome high interstitial fluid pressure, and distribute evenly throughout the tumor by slow diffusion. Compared to this complex process, the traditional EPR model is too simple to predict the enrichment of nanomedicine in tumors. In addition, the enrichment of nanomedicine in tumors is not only affected by the passive targeting effect of EPR, but also closely related to the active targeting functional groups of nanomedicines. It is especially critical that the type and size of the tumor also significantly affects the enrichment and therapeutic effects of the nanomedicine at the tumor site. Therefore, in-situ real-time monitoring of the absorption, distribution, metabolism and excretion process of nanomedicine in vivo and timely evaluation of therapeutic effects have become key issues in nanomedicine treatment.
The term “theranostics” was first proposed by John Funkhouser in 1998, which defined the integration of diagnosis and treatment as “theability to affect therapy or treatment of a disease state”. With the rapid development of the integration of diagnosis and treatment, its definition has been expanded more widely. It is now widely accepted that the integration of diagnosis and treatment is a new type of biomedical technology that combines the diagnosis or monitoring of diseases with treatment. In recent years, researchers have developed a series of nanomedicines that can integrate cancer diagnosis and treatment, bringing new hopes for humans to overcome cancer. The following is a brief introduction to the development of cancer diagnosis and treatment integration, and analyzes the special advantages of integration of diagnosis and treatment in the process of cancer diagnosis and treatment. Then, combined with the latest research progress, it introduces the construction and characteristics of various nano-medicine therapeutic agents, and finally looks into the integration of cancer diagnosis and treatment. Future development direction.
Advantages of cancer diagnosis and treatment integration
Because the integration of diagnosis and treatment integrates the diagnostic and therapeutic functions, it has obvious advantages over a single diagnosis or treatment. In particular, the integration of cancer diagnosis and treatment has great potential in patient stratification and personalized medicine, real-time monitoring of nano drug treatment process and feedback of nano drug treatment effects.
Patient stratification and personalized medicine
In conventional nanomedical research, researchers often focus on the effects of factors such as the composition, size, morphology, and surface modification of nanomedicine on the therapeutic effects of tumors, while often neglecting “patient stratification” of experimental animals. Because of individual differences, even in the same tumor model, tumors in different animals will have different amounts of nanomedicine intake. In basic research, xenografts are often used to grow smaller solid tumors on experimental animals, and tumor tissues are considered to be more homogeneous in such solid tumors. However, due to the differences in constitution among different animal individuals, the physiological characteristics of the tumor tissue, including the degree of fibrosis of the tissue and the density and structural integrity of the vascular system, are also different. This makes the EPR effect of tumor tissues in different individuals also have significant differences, which will affect the enrichment, retention and subsequent treatment effects of nanomedicine in tumor tissues (Fig. 1). For example, in a study by Karathanasis et al, iodine-labeled liposome nanoprobes were first injected into a rat of a breast tumor xenograft, and the ability of the tumor to nanomedicine uptake was evaluated by mammography. Then, according to the high and low intake of nanomedicine by the tumor, the rats were classified into the prognosis group and the poor prognosis group, and the rats in the two groups were treated with the same amount of doxorubicin-loaded liposomes. The study found that the two groups of rats showed significant differences in efficacy: the tumor growth rate of the prognosis group was significantly slower than the poor prognosis group. The results showed that even in the artificial xenograft tumor model, there were significant differences in the same tumor tissues between different individuals, and the difference in tumor physiological properties caused by this individual difference was more pronounced in large animals. For example, in a study of canines, sinus electron emission tomography-computed tomography (PET-CT) was used to track 64 Cu-labeled liposomes, and based on the EPR effect, nanomedicine was rich in tumor tissue. The set was effective in 6 of 7 cancers (Carcinoma, an epithelial-derived malignant tumor), and only 1 case was effective in 4 cases of sarcoma (non-epithelial-derived malignant tumor, sarcoma). Therefore, in basic research, it is necessary to more fully consider the impact of tumor heterogeneity. At present, based on the existing tumor models, it is necessary to develop more different types of tumor models, especially human-derived tumor models, in order to obtain more pre-clinical research data.
In clinical trials for human patients, the difference in tumor treatment effects caused by this individual difference is more pronounced and often manifests as a significant difference in mortality. In a clinical study of bowel cancer screening, Norwegian researchers followed up to 9.8678 million 50-64 year old volunteers for a period of 14.8 years (median time). Studies have shown that there is a significant gender difference in the impact of sigmoidoscopy on the incidence and mortality of bowel cancer: sigmoidoscopy can effectively reduce the incidence and mortality of male colorectal cancer, but it is not effective for women. The volunteers were divided into the following groups: 7.8126 million people did not do any screening; the remaining people were randomly assigned to two different screening groups, of which 102.27 million were only for sigmoidoscopy, and 102.81 million were for sigmoidoscopy. Check with the immunochemical fecal occult blood test. During the follow-up period, the incidence of bowel cancer and mortality in the screening group were 1.72% and 0.49%, respectively, both of which were significantly lower than the 2.50% and 0.81% of the control group. However, among women, the morbidity and mortality of the screening group were 1.86% and 0.60%, respectively, which were 2.05% and 0% of the control group. There was no significant difference in 59%. This suggests that gender is an important factor in tumor differentiation in human patients, and even the use of routine screening and stratification methods does not perfectly address the impact of individual differences in oncology. In another study of rectal cancer, the researchers found that the treatment recommended by the National Comprehensive Cancer Network (NCCN) guidelines is not necessarily effective for patients under 50 years of age. Surgical resection of stage I rectal cancer was performed as recommended by the NCCN guidelines, and total mesorectal resection combined with radiotherapy and chemotherapy was performed for stage II and III rectal cancer. The researchers found that the NCCN guidelines are generally instructive. For patients with stage I and stage II and III who are over 50 years of age, the survival rate of patients treated with the guidelines is higher than that of patients who did not follow the guidelines. Especially for patients with stage II and III who are over 50 years of age, the recommended treatments can increase survival by 14%. However, for patients with stage II and III under 50 years of age, whether or not they follow the guidelines has no significant effect on their survival rate. This result suggests that for patients under the age of 50, appropriate reductions in chemotherapy can be considered to reduce associated side effects and complications and improve their quality of life. Moreover, such tumor variability due to individual differences cannot be avoided even with cutting-edge treatments. In a recent immunotherapy study, the researchers found that using PD-1 antibodies as immunological checkpoint inhibitors to activate T cells in the autoimmune system to kill tumor cells is not suitable for all populations. The study found that in addition to the T cells that kill tumor cells, there are a large number of tumor-independent T cells for virus recognition, and these T cells do not act on tumor cells. The ratio directly affects the effectiveness of immunotherapy. In tumor tissues of cancer patients with poor prognosis, such T cells that recognize viruses account for a greater proportion. The results of the study indicate that the physiological characteristics of the tumor, including EPR effect, oxygen content and autoimmune system, have significant individual differences, which directly affect the therapeutic effects of various tumors. The use of antibodies as immunological checkpoint inhibitors to activate T cells in the autoimmune system to kill tumor cells is not suitable for all populations. The study found that in addition to the T cells that kill tumor cells, there are a large number of tumor-independent T cells for virus recognition, and these T cells do not act on tumor cells. The ratio directly affects the effectiveness of immunotherapy. In tumor tissues of cancer patients with poor prognosis, such T cells that recognize viruses account for a greater proportion. The results of the study indicate that the physiological characteristics of the tumor, including EPR effect, oxygen content and autoimmune system, have significant individual differences, which directly affect the therapeutic effects of various tumors. The use of antibodies as immunological checkpoint inhibitors to activate T cells in the autoimmune system to kill tumor cells is not suitable for all populations. The study found that in addition to the T cells that kill tumor cells, there are a large number of tumor-independent T cells for virus recognition, and these T cells do not act on tumor cells. The ratio directly affects the effectiveness of immunotherapy. In tumor tissues of cancer patients with poor prognosis, such T cells that recognize viruses account for a greater proportion. The results of the study indicate that the physiological characteristics of the tumor, including EPR effect, oxygen content and autoimmune system, have significant individual differences, which directly affect the therapeutic effects of various tumors.
Individual differences make uniform standardized treatments not optimal for different cancer patients, so personalized medicine has become the trend. According to the explanation given by MD Anderson Cancer Center, the world’s leading personalized medical institution, personalized medicine as a cancer treatment strategy, its core idea is based on various tumor markers and tumor cell treatment The response, analyzing the patient’s likelihood of responding to a particular treatment, combined with consideration of the patient’s genetic factors may lead to different manifestations of drug metabolism, response and toxicity, while synthesizing the patient’s tumor molecular profile, tumor site and other physiological characteristics, Develop a set of optimal treatment options for individuals. As can be seen from the above definitions, in personalized medicine, various types of diagnosis and treatment need to be organically integrated throughout the treatment process, which fully coincides with the concept of integration of cancer diagnosis and treatment, thus developing fusion diagnosis and treatment. The integrated cancer diagnosis and treatment technology will strongly promote the development of personalized medicine.
Real-time monitoring of nanomedicine treatment processes
In the treatment of tumors, the distribution of nanomedicine in tumor tissues is directly related to curative effect, so this is also a key issue to be considered in the development of nanopharmaceuticals. However, the distribution of nanomedicine is closely related to various physiological characteristics of the tumor (such as interstitial fluid pressure, support tissue thickness, and vascular density). For the central region of tumor tissue, nanomedicine is generally more difficult to diffuse, and tumor cells in such central regions tend to have stronger carcinogenic ability and are prone to cause tumor recurrence. Because all kinds of living microscopic imaging techniques have good temporal and spatial resolution, in the development of nanomedicine, these imaging techniques are often used to study the distribution of nanomedicines in tumor tissues and analyze them with tumor tissues. interaction. In a study of temperature-sensitive liposome-loaded chemotherapeutic drug doxorubicin, the researchers observed that the red-fluorescence of doxorubicin itself at about 590 nm found that this temperature-controlled release of doxorubicin could effectively improve The distribution of mycin in the central part of tumor tissue provides a new idea for improving the therapeutic effect and reducing toxic side effects of doxorubicin-based chemotherapeutic drugs. In another study of the transport process of nanomedicines, researchers used live laser confocal scanning microscopy to observe the transport of micellar particles in tumors, subverting the traditional view that tumor vascular permeability is a single static process. In addition to the static transport process of the vascular wall space, the permeability of tumor blood vessels also includes another dynamic “eruption” process in which the vessel wall bursts and forms a transient, intense outward fluid flow. Thus, the micelle particles enter the tumor stroma, and these random “eruptions” can explain the enhanced extravasation of the nanomedicine in the tumor blood vessels. In summary, in vivo microscopic imaging technology can monitor nanomedicine treatment processes in real time.
However, in the course of clinical treatment, considering the invasiveness of some microscopic imaging techniques, it is often not directly applied to the human body, instead it is magnetic resonance imaging (MRI), X-ray computed tomography (X-ray). CT), positron emission computed tomography (PET), ultrasound imaging (USI) and other structural or functional imaging techniques. For example, the researchers assembled a clinically approved sulphate-based MRI contrast agent (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) and a platinum-based chemotherapeutic drug (Dichloro(1,2-Diaminocyclohexane) Platinum(II), DACHPt) in polymer micelles. As a nano-diagnostic agent, MRI can be used to track the distribution of nano-medicine in the tumor. The X-ray spectrum of platinum further confirms that the chemotherapeutic drug is consistent with the tumor tissue distribution of the MRI contrast agent. The study showed that the co-loading of existing contrast agents with anti-cancer drugs in the same nanoparticle is an effective method for the development of nano-diagnostic agents. Nanomedicine can not only reveal its real-time distribution in tumor tissues, but also monitor the controlled release of anticancer drugs in tumor tissues. For example, the manganese-based or gadolinium based MRI contrast agents, T . 1 intensity-weighted images closely related to the manganese ions or an aqueous environment around the gadolinium ion, may thus simultaneously coated with liposome MRI contrast agents and anti-cancer drugs, in liposomes burst release anti-cancer drug, or manganese-based MRI contrast agent gadolinium group is simultaneously released into the aqueous environment, causing T . 1 weighted image significantly enhanced strength, can be used to monitor release process nano anticancer drug treatment agent .
In addition, nanomedicines can also be used for activatable tumor therapy. In the aforementioned therapeutic agents, the therapeutic effects are usually chemotherapeutic drugs, which directly act on tumor cells and do not require external stimulus activation. In order to reduce the side effects of anticancer drugs and optimize their controllability, the researchers developed new tumor treatment methods based on external stimuli such as photodynamic therapy and photothermal therapy. In photodynamic therapy and photothermal therapy, nanomedicine generates an active oxygen species or a thermal effect with a cell killing effect under the illumination of external excitation light, thereby controllably killing tumor cells. Since these nanomedicines have tumor killing effects only under specific external stimuli, choosing the best external stimulation timing is crucial for subsequent therapeutic effects. The enrichment of nanomedicine at the tumor site is a dynamic process, first based on passive or active targeting in tumor tissue enrichment, and then removed from the tumor tissue with metabolic processes. The best tumor killing effect is obtained only when the nanomedicine is activated at the highest concentration of the tumor tissue. In order to reduce the damage of the treatment to normal tissues, the concentration of nanomedicine in normal tissues is also critical. Therefore, in order to develop an optimal treatment plan, it is necessary to comprehensively consider the concentration changes of nano drugs in tumor tissues and normal tissues to obtain better therapeutic effects and low side effects. Using nano-medicine to integrate imaging and therapeutic functions, you can grasp the dynamic distribution of nano-drugs in tumor tissues in real time, so as to grasp the optimal timing of stimulation. For example, in a study of porphyrin self-assembled nanomedicines, the researchers labeled 64 Cu on porphyrins for PET imaging, and porphyrin itself acts as a photothermal treatment. By detecting the distribution signal of 64 Cu, the researchers found that the concentration ratio of nano-medicine in tumor tissue and normal tissue was 6:1, and chose the stimulation window at this time to obtain the optimal therapeutic effect.
Feedback nano drug treatment effect
The use of nano-diagnostic agents to timely feedback the therapeutic effects of nano-drugs is conducive to timely adjustment of treatment plans based on the latest development of the disease. In basic research, the evaluation of the therapeutic effect of nanomedicine is usually performed by measuring the volume of tumor tissue in an animal model. However, such feedback means are not suitable for clinical applications, especially for tumors deep in tissues or internal organs. Therefore, it is particularly important to develop a new means of timely feedback on the therapeutic effects of nanomedicine. Many of the physiological characteristics of the tumor tissue microenvironment are different from normal tissues, including lower pH and hypoxic environment. These physiological indicators also reflect changes in tumor tissue. For example, combining a pH indicating molecule or an oxygen content indicating molecule with an anticancer drug is expected to promptly feedback the therapeutic effect of the nano drug. In order to achieve timely feedback of therapeutic effects, the indicator molecules need to have the following characteristics: First, this requires that the indicator molecules have different targeting functions from the anticancer drugs, and each of them works independently and does not affect each other within the tumor tissue. More importantly, the indicator molecule is required to have a relatively long tumor retention time. This is because the indicator molecule and the anticancer drug are required to reach the tumor site at the same time, and the tumor treatment cycle takes a certain time, and the tumor microenvironment is also a slow change. The process, therefore, requires the indicator molecule to remain in the tumor tissue over a longer period of time, thereby ensuring that the therapeutic effect of the feedback is sustained.
In view of the difficulty in designing and preparing nano-diagnostic agents with therapeutic feedback function, it is often used in a step-by-step manner, first using anticancer drugs, and after a period of time, various indicator molecules are used to test the therapeutic effect. For example, in a study evaluating the efficacy of the anticancer drug Everolimus in patients with metastatic renal cell carcinoma, the researchers used 89 Zr-bevacizumab tracer molecules to evaluate treatment effects using PET imaging. By collecting PET images of 13 patients in Everolimus for 2 and 6 weeks, and comparing with pre-medication, the results showed that 89 Zr-bevacizumab tracer molecules can effectively reflect the effect of Everolimus on tumor treatment.
Although there are still many difficulties in using the nano-medicine to feedback the efficacy of tumors, some of the latest research results in encouraging scientists to continue to forge ahead. For example, a temperature indicator is combined with a photothermal material to design a photothermal nano-diagnostic agent that can feed back the treatment temperature. In this study, the researchers used a different sensitivity of the different luminescence levels of the up-converting nanomaterials to the temperature, and designed a proportional temperature indicator that varies linearly with the relative intensity of the emission peaks. The researchers applied a layer of carbon nano-layer with photothermal effect on the surface of the up-converted nanomaterial to prepare a photothermal nano-diagnostic agent. The temperature of the photothermal therapy was obtained by observing the relative intensity of different emission peaks of the temperature indicator. Although this nano-diagnostic agent can not directly feedback the therapeutic effect, since the temperature of photothermal therapy determines the effect of tumor treatment, it can play an indirect feedback role. This research fully reflects the feedback effect of nano-medicine therapeutic agents. Advantage.
Construction of nanometer therapeutic agents
The core technology for the integration of diagnosis and treatment of cancer lies in the rational design of nano-medicine agents, and the integration of diagnostic agents and therapeutic agents into the same carrier nanoparticle is the basic idea for constructing nano-medicine therapeutic agents
Common medical imaging contrast agents mainly include fluorescent contrast agents, nuclear magnetic contrast agents, X-ray contrast agents, radionuclide contrast agents, ultrasound contrast agents, etc.
1) Fluorescent contrast agent. Since optical signals have good controllability and are easily captured and resolved, optical signal-based diagnostic and imaging techniques are widely used in the integration of diagnosis and treatment. Fluorescent signals are the most commonly used optical signals. Researchers have developed a variety of fluorescent contrast agents by adjusting the fluorescence of various fluorescent molecules or nanoparticles, including common organic fluorescent dyes, quantum dots, and rare earth doped nanoparticles.
Organic fluorescent dyes are a class of small organic molecules that produce fluorescent emissions under specific wavelengths of light. There are many kinds of organic fluorescent dyes, and currently used are fluorescein, rhodamine, cyanine dye and BODIPY dye. Organic fluorescent dyes generally have high quantum yield, large half-peak width and easy to adjust excitation and emission wavelengths, extremely short fluorescence lifetime, small molecular weight and good biocompatibility. However, organic fluorescent dyes are often subject to their relatively poor photostability, which is not conducive to long-term fluorescence monitoring of pathological changes in tumor tissues. Improving the light stability of organic fluorescent dyes is one of the hotspots of current research. In addition, redshifting the excitation and emission of organic fluorescent dyes to the infrared region is also advantageous for its application in the biomedical field. This is due to the better tissue penetration properties of infrared light relative to ultraviolet and visible light, extending the application of organic fluorescent dyes in deep biological tissues. Among them, the development of organic fluorescent dyes with infrared II region fluorescence performance has become a research hotspot. In addition, the development of organic fluorescent dyes with biological small molecule response, capable of monitoring dynamic physiological reactions in biological tissues, is of great significance for the integration of diagnosis and treatment of cancer. At present, it is common to include an adenosine triphosphate responsive dye, an oxygen content indicator dye, and a pH indicator dye which can be used in a living body. For example, the researchers developed a pH-responsive fluorescent contrast agent designed to have the characteristics of aggregation-induced luminescence (AIE), which carries a negative charge and shows very weak fluorescence under physiological conditions; in acidic tumor tissue The surface of the nano-diagnostic agent is converted into a positive charge, and aggregates to produce a luminescent effect, realizing fluorescence imaging of tumor acid environment activation.
A quantum dot is a nanoscale semiconductor. Due to the quantum confinement effect, its continuous energy band splits the discrete energy level and can generate fluorescence emission under the excitation of excitation light. Compared with organic fluorescent dyes, quantum dots have better photostability, and their emitted light intensity is not weakened by the long-term illumination of the excitation light. Moreover, the half-peak width of the emission peak of the quantum dot is narrow, which can effectively avoid overlapping of emission spectra, and is more advantageous for multi-channel detection or imaging applications. The position of the emission peak of the quantum dot is easy to adjust, and different emission peaks from the visible region to the near-infrared region can be obtained by changing the size of the quantum dot. For example, the emission peak of a cadmium selenide quantum dot is red-shifted as the particle diameter increases, and the red luminescence from the blue luminescence to the 8 nm particle size at a particle diameter of 2 nm. Since the excitation peak of the quantum dot is generally in the ultraviolet region, the Stokes shift between the emitted light and the excitation light is large, which is advantageous for eliminating the interference of the excitation light in biomedical imaging, and collecting the fluorescent signal more easily. Similar to organic fluorescent dyes, the fluorescence lifetime of quantum dots is generally small, about 10 ns. In order to obtain more biocompatible quantum dots, the researchers have developed a series of quantum dots based on other elements based on the preparation of quantum dots using conventional IV, II-VI, IV-VI or III-V elements. Nanoparticles, in which carbon dots (CDs) are one of the research hotspots. Carbon quantum dots not only have the luminescent properties and quantum confinement effects of traditional quantum dots, but also have the advantages of good water solubility, low biotoxicity and good electrical conductivity. Therefore, they have broad application prospects in biological detection and medical imaging.
Rare earth doped nanoparticles are also a common class of optical contrast agents. The rare earth ions in these nanoparticles have abundant energy levels and are capable of absorbing excitation light to generate electron transition emission fluorescence. Due to the long energy lifetime of rare earth ions, the rare earth doped nanoparticles have a longer fluorescence lifetime, usually up to the order of ms, which is also an advantage of their use as an optical contrast agent based on fluorescence lifetime imaging technology. According to the energy of the excitation photons and the emitted photons absorbed by the rare earth doped nanoparticles, the upconversion luminescence nanoparticles are called the upconversion luminescence nanoparticles, and the upconversion luminescence nanoparticles are larger. . Usually, some energy is lost in the form of heat during the electronic transition, so that the photon energy of the emitted light is usually lower than the photon energy of the excitation light, so down-conversion luminescence is a common fluorescent phenomenon. The study of upconversion was first reported in 1959. Bloembergen first proposed the mechanism of excited state absorption in the study of infrared quantum detectors, that is, the substance is first excited after absorbing one photon, and then the substance in the excited state is reabsorbed. The photon is placed in a higher excited state, and the photon energy emitted by the photon is greater than the photon energy of the excitation photo, that is, two or more excitation photons with less energy are converted into a larger energy emission photon. Rare earth doped upconversion nanoparticles (eg NaYF 4 :Yb, Er/Tm/Ho, NaLuF 4 :Yb, Er/Tm, NaYF 4: Nd, Yb, Er/Tm/Ho, etc.) are relatively mature upconversion luminescent materials. This is because there are a large number of semi-stable intermediate levels in the rare earth ions that can last for a plurality of photon absorptions, thereby obtaining a high up-conversion efficiency. With the continuous development of up-conversion luminescent materials, the up-conversion luminescence mechanism has been supplemented more comprehensively. Generally speaking, the mechanism of up-conversion luminescence can be summarized into three types: excited state absorption up-conversion, energy transfer up-conversion and photon avalanche. In recent years, the application of rare earth doped upconversion nanoparticles as a novel optical contrast agent in biological detection and medical imaging has received increasing attention. Compared with traditional fluorescent labels, rare earth doped upconversion nanoparticles have the advantages of low toxicity, good chemical stability, good light stability, narrow half-peak width of emission peaks and large anti-Stokes shift. In addition, the biggest advantage of rare earth doped upconversion nanoparticles is that they use infrared light as excitation light, which can avoid the interference of autofluorescence of biological samples under the excitation condition, thereby reducing the detection background and improving the signal to noise ratio. Therefore, upconversion nanoparticles as biomarkers have broad application prospects in the fields of biology, medicine and life sciences.
2) Nuclear magnetic contrast agent. Magnetic resonance imaging (MRI) is a commonly used imaging and diagnostic technology in clinical practice, and is also widely used in the development of integrated diagnosis and treatment technology. MRI is based on the different attenuation of the released energy in different structural environments inside the material. The electromagnetic wave emitted by the gradient magnetic field is detected to detect the position and type of the nucleus of the object, and the structural image of the object is drawn accordingly. . Magnetic nanomaterials can be used in MRI contrast agents, which are significantly different from human tissue under gradient magnetic fields, resulting in contrast-enhanced images. Common MRI contrast agents include iron-based metal oxides, manganese metal oxides, and rare earth ion complexes (such as ruthenium complexes). By introducing a substance having a tumor therapeutic function on a magnetic nanomaterial, the purpose of integration of diagnosis and treatment can be achieved. For example, the researchers designed a hollow core-shell structure of MnO@Mn 3 O 4 , in which the Mn 3 O 4 cavity can be loaded with the chemotherapy drug doxorubicin, and the manganese metal oxide as an excellent T 1 -weight contrast agent can be realized based on Integration of MRI and chemotherapy. In another study, the researchers designed FePt alloy nanoparticles, which can be used as MRI contrast agents, and the Pt that slowly exudes in the particles also has tumor killing function and ion therapy.
3) X-ray contrast agent. X-ray based medical imaging techniques are also widely used clinically. X-ray contrast agents can enhance the contrast of images by using the stronger attenuation effect of heavy atoms on X-rays. Common X-ray contrast agents usually contain heavy atoms with a large atomic number, such as gold nanoparticles and nanoparticles doped with elements such as ruthenium, tungsten, and rhenium. For example, the researchers used gold’s heavy atomic effect to develop folate-modified gold nanorods for X-ray imaging-guided tumor diagnosis and treatment. Gold nanorods have a good X-ray absorption effect, so they have good X-ray imaging capabilities, and can also be used as sensitizers for radiation therapy. At the same time, gold nanorods have good photothermal conversion efficiency in the infrared region, and can also be used for photothermal treatment of tumors. In the end, it is expected to achieve X-ray imaging guided radiotherapy and photothermal synergy.
4) Radionuclide contrast agent. Radionuclide contrast agents are mainly used in PET and single-photonemission computed tomography (SPECT). These two imaging techniques mainly use radioisotopes with appropriate half-life as contrast agents, and release gamma rays due to radioactive decay. And the method of obtaining the detection signal. PET/SPECT images can be achieved using radionuclide labeled nanodiagnostic agents. For example, using the human body’s bio-pigment, melanin, as a raw material, the magnetic melanin nanoparticles were successfully synthesized by biomimetic method, and then the characteristics of metal ions adsorbed by melanin were utilized to realize the rapid one-step radionuclide 64 Cu 100% mark. Labeled nanoprobes can simultaneously target tumors using three imaging modalities: PET, MRI, and photoacoustic imaging (PAI). In addition, melanin has a strong absorption of light in the near-infrared region, and has excellent photothermal conversion efficiency. The probe can achieve high-efficiency tumor photothermal treatment effect after accumulating in the tumor site with low laser irradiation. Multimodal imaging guided photothermal therapy.
5) Ultrasound contrast agent. Ultrasound imaging is the use of ultrasonic sound beams to scan the human body, using different absorption and reflection of ultrasonic waves by different human tissues, and receiving ultrasonic reflection signals to obtain images of tissue in the body. At present, the main ultrasound contrast agent used in the clinic is ultrasonic microbubbles, which vibrate under the action of ultrasound and scatter strong ultrasonic signals. Especially when the frequency of incident sound waves is consistent with the bubble resonance frequency, the energy of the incident sound waves is all bubbles. Resonance absorption, forming resonance scattering, thereby increasing its contrast in ultrasound imaging. Common ultrasound microbubbles are usually large in size (on the order of μm) and thus difficult to pass through the pulmonary circulation, limiting their use in the integration of diagnosis and treatment. In order to solve this problem, the researchers designed and prepared a photo-responsive biodegradable nano rattle, and simultaneously loaded gold nanorods with perfluoro-n-pentane into mesoporous silica to realize photo-responsive tumor diagnosis and treatment integration. Using the photothermal effect of gold nanorods, the perfluoro-n-pentane in the cavity structure is rapidly vaporized, resulting in microbubbles with excellent contrast-enhanced ultrasound, and at the same time achieving photothermia treatment of cancer. In addition, the use of mesoporous silica as a carrier not only prolongs blood circulation time, but also biodegrades to reduce toxicity in vivo. By using the ingenious synergy of gold nanorods and perfluoro-n-pentane under illumination conditions, the intelligent photoresponsive ultrasound and photoacoustic multimodal imaging guided tumor photothermal therapy was finally realized.
6) Photoacoustic imaging contrast agent. Photoacoustic Imaging (PAI) is a new hybrid imaging technology that combines optical and ultrasonic imaging techniques with high contrast in optical imaging and high spatial resolution in ultrasound imaging. The imaging principle is based on the acoustic signal of the MHz frequency generated by the thermoelastic expansion of endogenous substances (such as water, melanin, collagen and lipids) or exogenous photoacoustic imaging contrast agents in biological tissues after absorption of laser pulses. By detecting these acoustic signals, image reconstruction can be performed for diagnostic or imaging purposes. Compared with optical signals, biological tissue scatters less acoustic signals, so the application of photoacoustic imaging technology can break the imaging depth limit of traditional optical imaging. In general, optical imaging is difficult to apply to tissues with an imaging depth of about 1 cm, while imaging depth of photoacoustic imaging is reported to be about 5 cm. As a rapidly developing non-invasive imaging technology, photoacoustic imaging has been widely used in biomedical imaging and disease diagnosis from cell to organ. As a contrast agent for photoacoustic imaging, it is required to have good photothermal conversion efficiency. Common photoacoustic imaging contrast agents include excellent photothermal conversion inorganic nanomaterials such as gold nanoparticles, copper sulfide, black phosphorus, and a series of organic polymer nanomaterials such as polymer semiconductors. Based on the excellent photothermal conversion function of such materials, it has the function of photothermal therapy itself, and thus can be directly used as a nanometer therapeutic agent. For example, the researchers used the internal cavity structure of ferritin as a nanoreactor to successfully prepare a copper sulfide-ferritin nanometer therapeutic agent by biomimetic synthesis. With its efficient photothermal conversion performance, effective photoacoustic imaging and photothermal therapy can be achieved. At the same time, in the synthesis process, the radionuclide 64 Cu is incorporated as a raw material and can also be used for PET imaging. In addition, Zhou et al. used self-assembly of polydopamine-coated gold nanoclusters to form black-body nanomaterials with broad-spectrum absorption properties, which have excellent photothermal conversion efficiency in both infrared I and infrared II regions, and can realize light in infrared region II. Acoustic imaging guided photothermal therapy. Since the excitation light of the infrared region II has better tissue penetration performance, less phototoxicity and higher maximum allowable energy density in biological applications, it has a better application prospect than the infrared region I excitation light.
Commonly used cancer therapeutics include chemotherapy drugs, radioactive sources, photosensitizers, photothermal nanoconverters, therapeutic genes, immunological checkpoint inhibitors, etc.
1) Chemotherapy. Chemotherapy, as one of the traditional cancer treatment methods, is widely used in the research of tumor diagnosis and treatment integration. Chemotherapy drugs treat cancer primarily by blocking tumor cell division. Common chemotherapeutic drugs include doxorubicin (DOX), paclitaxel (PTX), docetaxel (Dtxl), and cisplatin (CDDP). However, since these chemotherapeutic drugs are usually rapidly cleared by the human body and are often distributed unevenly in tumor tissues, their therapeutic effects are severely reduced. At the same time, in addition to acting on tumor tissues, chemotherapeutic drugs also have a killing effect on normal tissues, and thus inevitably bring about large side effects. In addition, long-term use of chemotherapy drugs can cause strong resistance of tumor cells, and will also reduce its therapeutic effect. As mentioned above, the integration of diagnosis and treatment can observe the distribution of chemotherapy drugs in the tumor site and the metabolic process in real time, so it can timely understand whether the chemotherapy drugs are evenly distributed and whether there is drug resistance, and at the same time detect its distribution in normal tissues to effectively control the chemotherapy drugs. Side effects. For example, the researchers synthesized a radionuclide 64 Cu-labeled doxorubicin polydopamine (PDA)-钆-metal fullerene core-satellite nano-therapeutic agent with good biocompatibility and strong near-infrared absorption. And good MRI function. Under the irradiation of excitation light, polydopamine undergoes photothermal conversion, which can be used for both photothermal therapy and stimulating the release of doxorubicin for chemotherapy. In the end, the nano-diagnostic agent effectively achieved the photothermal and chemotherapy synergistic treatment guided by MRI/PAI/PET multi-modal imaging.
2) Radiotherapy. Radiotherapy is a method of treating cancer by using a radioisotope as a therapeutic agent. Radiotherapy can be divided into internal radioisotope therapy (IRT) and external beam radiation therapy (EBRT) depending on the location of the radiation source. Radioisotope treatment Injects radioisotopes (such as 131 I, 177 Lu, 90 Y, 188 Re, etc.) into the body by minimally invasive injection , using active or passive targeting processes to enrich tumor tissue and inhibit tumor cell tissue growth. However, it still inevitably has a killing effect on normal tissues and causes side effects. External beam therapy is stimulated by an external source of ionizing radiation for the precise treatment of solid tumors deep in the tissue, such as breast, lung, colorectal, and brain tumors. According to the different radiation sources, it can be divided into proton therapy, heavy ion therapy and X/γ radiation therapy. Among them, the most widely used clinically is X-ray treatment. The therapeutic effect of radiotherapy is greatly affected by the oxygen content of tumor cells. Generally, tumors with higher oxygen content have better radiotherapy effects. In the process of radiotherapy, monitoring the oxygen content of tumor tissue is of great significance, so it is very important to develop the corresponding integrated diagnosis and treatment technology.
3) Photodynamic therapy. Photodynamic therapy is a new type of tumor treatment method that uses a photosensitizer to produce cytotoxic reactive oxygen species under the stimulation of excitation light to achieve tumor tissue killing. Photodynamic therapy has been clinically approved for the treatment of cancers such as esophageal cancer, skin cancer and non-small cell lung cancer. Since the excitation light has good space-time selectivity, the photosensitizer can be specifically concentrated at the tumor site to generate active oxygen species, thereby effectively preventing damage to normal tissues. Photodynamic therapy can usually be divided into two types of photodynamic therapy, type I and type II. In type I photodynamic therapy, the triplet state of the photosensitizer reacts with environmental species to form free radical anions or cations. These radicals can be further reacted with triplet oxygen ( 3 O 2 ) or water to form superoxide anion (O 2 ·- ) or hydroxyl radical (·OH). In type II photodynamic therapy, the triplet state of the photosensitizer can transfer its energy to 3 O 2 to produce singlet oxygen ( 1 O 2 ). Organic photosensitizers (such as porphyrins and phthalocyanines) usually convert oxygen to 1 O 2 by type II photodynamic therapy, and thus strongly depend on the oxygen content in tumor tissues, which is not conducive to the treatment of hypoxic tumors. In contrast, some inorganic photosensitizers (such as TiO 2 , ZnO, and W 18 O 49Etc.) The production of ·OH by type I photodynamic therapy does not require oxygen to participate and is therefore still effective in hypoxic tumors. As described above, since the excitation light intervention time of photodynamic therapy needs to be effectively coordinated with the distribution of the photosensitizer in the tumor tissue, achieving integration of diagnosis and treatment is of great significance for improving the efficacy of photodynamic therapy. For example, the researchers used magnetic nanoparticles as a carrier for the photosensitizer chlorin e6 (Ce6) to achieve fluorescence imaging and MRI-guided photodynamic therapy.
4) Photothermal therapy. Photothermal therapy is also a treatment method for tumors that requires external light excitation. Compared with photodynamic therapy, photothermotherapy replaces the photosensitizer that produces reactive oxygen species with a photothermal conversion agent with excellent photothermal conversion photothermal conversion efficiency, and uses excitation light to excite photothermal conversion agent to generate heat for killing tumors. organization. In order to improve the therapeutic effect of photothermal therapy, it is critical to develop a highly efficient photothermal conversion agent. In addition to improving its tumor targeting and reducing its own biological toxicity, the researchers also hope to develop a photothermal conversion agent with strong infrared absorption and high conversion efficiency, which is conducive to expanding the tissue suitable for photothermal therapy. depth. Commonly used photothermal conversion agent nanomaterials include gold-based nanomaterials (such as gold nanorods, gold nanocage, etc.), carbon-based nanomaterials (such as carbon nanotubes, carbon quantum dots, etc.), metal sulfides (such as CuS, WS 2). Etc.) Organic dyes that absorb infrared light (such as phthalocyanine green (ICG), IR825, etc.), black phosphorus, and polymer nanoparticles (such as polypyrrole, polyaniline, etc.). Such photothermal conversion nanomaterials have excellent photoacoustic imaging functions, and can realize integration of diagnosis and treatment. For example, two-dimensional transition metal carbonitrides, as a new type of photothermal conversion material, are widely used in the diagnosis and treatment of tumors. The researchers used the heavy atom effect of the Ta element in Ta 4 C 3 to be used for CT imaging, and it has excellent photothermal conversion efficiency, and finally achieved photothermal therapy guided by CT/PA imaging.
5) Gene therapy. As a new treatment method, gene therapy uses a vector to input therapeutic genes into the body, compensate for abnormal genes and express specific proteins or interfere with the expression of abnormal genes to achieve the purpose of treating tumors. Common gene therapy is achieved by: (1) gene-enhancing therapy, transporting healthy genes into cells to replace mutants; (2) gene suppression therapy, introducing a novel gene that inhibits the expression of diseased genes or rendering functions Normal gene inactivation; (3) Gene-mediated tumor killing therapy, which delivers therapeutic genes to tumor cells and triggers apoptosis. Since therapeutic genes usually require nanocarriers for in vivo transport, in order to achieve integration of diagnosis and treatment, materials having imaging or diagnostic functions can be transported on the carrier. For example, siRNA is loaded on mesoporous silica-coated upconverting nanoparticles as a nano-diagnostic agent. Under infrared light excitation, the ultraviolet light generated by up-converting nanoparticles can activate siRNA and inhibit tumor growth. At the same time, the 800 nm infrared luminescence peak of upconverting nanomaterials can also be used to monitor the distribution of nanomedicines in tumor tissues, and it is expected to achieve fluorescence imaging-guided tumor gene therapy.
6) Immunotherapy. Immunotherapy is a method of tumor treatment that activates the body’s immune system through external stimuli. Immunotherapy usually works in three ways: (1) designing monoclonal antibodies to enhance immune response and killing tumor cells; (2) using immune checkpoint inhibitors to help the immune system recognize and attack tumor cells; (3) synthesizing tumor vaccines To elicit an immune response for the treatment and prevention of cancer. Since immunotherapy kills tumor cells by activating the immune system, side effects are small; and since the human immune system has a memory function, the therapeutic effect of immunotherapy can exist for a long time to control tumor recurrence. Similar to gene therapy, immunotherapy also relies on drug delivery and drug distribution, so achieving integration of care and treatment is important to improve the therapeutic effect of immunotherapy. In immunotherapy, it is generally required to transport a therapeutic antibody, an immunological checkpoint inhibitor, and the like into the body using a nanocarrier, and thus a material having an imaging or diagnostic function can be co-transported in the carrier to realize integration of diagnosis and treatment. For example, the use of 89 Zr-deferoxamine labeled anti CD8 Cys- diabodies ( 89 Zr-Mal-cdb the DFO-169) for non-invasive PET endogenous immune CD8-positive T cells in tracking. Studies have found that PET can be used to track endogenous CD8-positive T cells and observe their role in tumor tissue.
Nanomedicines require both imaging and therapeutic functions, requiring the same nanoparticle to be multifunctional. In addition to some of the multifunctional nanomaterials can be directly used as nano-diagnostic agents, more nano-diagnostic agents are realized by simultaneously loading diagnostic agents and therapeutic nano-materials in nano-carriers, which are generally classified into organic nano-materials. The carrier, the inorganic nanocarrier, and the organic-inorganic hybrid nanocarrier.
1) Organic nanocarriers. Organic nanocarriers have good biocompatibility and are widely used in biomedical fields. Common organic nanocarriers include liposomes, polymersomes, polymer nanoparticles, dendrimers, and the like. These vectors can be loaded to image or treat the payload by physical entrapment or chemical binding. Lipid small molecules or amphiphilic polymers can be assembled into liposomes or micellar structures, using internal hollow spaces to load hydrophilic or hydrophobic (determining the hydrophilicity or hydrophobicity of the inner surface of the nanomaterials) and Therapeutic agent. For example, Ryu et al. designed and synthesized N-(2-hydroxypropyl)-methacrylamide copolymer-Gly-Phe-Leu-Gly-DOX block molecules, which can be used for different hydrophilic and hydrophobic properties of their own blocks. Self-assembly into a micellar nano-diagnostic agent, wherein the hydrophobic chemotherapy drug doxorubicin molecule is located in the center of the micelle, and the hydrophilic end is located on the surface of the micelle to ensure its dispersibility in water, and the integration of diagnosis and treatment can be realized. In addition, the researchers designed and developed a tumor in situ fixed-site self-assembly technique, which can effectively avoid the uptake of ICG by reticuloendothelial system-rich organs by using alkaline phosphatase response peptide and ICG with the help of endogenous phosphatase. Specifically, the tumor tissue is co-assembled to form nanofibers, and the nanofiber structure can significantly increase the accumulation efficiency of ICG in the tumor site, prolong its residence time, and finally realize the photodynamic/light guided by fluorescence/photoacoustic dual mode imaging. Thermal combination therapy.
2) Inorganic nanocarriers. Inorganic nanocarriers have good structural stability, and most of the inorganic nanocarriers are not easily degraded in the body, which may cause long-term retention problems in the body. Currently used inorganic nanocarriers include mesoporous silicon nanoparticles, calcium phosphate or calcium carbonate nanoparticles, and hollow structure gold nanoparticles. As described above, the mesoporous silicon-coated gold nanorods are used to load the ultrasonic microbubble liquid precursor, and the microbubble liquid precursor is vaporized by photothermal conversion, and ultrasonic microbubbles are generated in situ in the tumor tissue for ultrasonic imaging. At the same time, photon imaging and photothermal therapy are realized by using gold nanorods. In addition, the researchers designed hollow silica for loading glucose oxidase and arginine, using glucose oxidase to consume glucose in tumor cells to achieve hunger-like treatment, while the oxidation process produces hydrogen peroxide, which reacts with arginine. Nitric oxide is produced to help hydrogen peroxide kill tumor cells. The researchers also used hollow calcium carbonate nanoparticles to load manganese-based nanoparticles and second-generation photosensitizer Ce6, and coated polydopamine on the surface of calcium carbonate nanoparticles for photodynamic therapy guided by MRI/PAI multimodal imaging. In addition, some two-dimensional nanomaterials, such as graphene, black phosphorus and two-dimensional transition metal carbonitrides, can be combined with imaging agents by surface modification to introduce functional groups (such as carboxyl groups, amino groups, etc.) or electrostatic adsorption effects. And therapeutic materials for the integration of diagnosis and treatment of tumors. For example, the researchers constructed Ti 3 C 2 -doxorubicin-soybean phospholipid nanomedicines by electrostatically adsorbing layers on the Ti 3 C 2 surface . In the nanometer therapeutic agent, photoacoustic imaging and photothermal therapy are realized by the photothermal conversion function of the two-dimensional transition metal carbonitride Ti 3 C 2 , and the chemotherapeutic drug doxorubicin is loaded as a carrier to realize photoacoustic imaging. Guided photothermal-chemotherapy synergistic treatment.
3) Organic-inorganic hybrid nanocarriers. Single organic or inorganic nanocarriers have their own advantages and disadvantages. In order to overcome their respective defects, it is a research hotspot to construct organic-inorganic hybrid nanocarriers by hybridizing organic and inorganic materials. Organic-inorganic hybrid nanocarriers can have their own advantages. For example, the inorganic components can provide good light stability, thermal stability and mechanical stability, and can form various types of cavities (such as mesoporous type, Hollow and rattle types, etc.) are used for nano drug loading, and their organic components can effectively regulate their affinity/hydrophobicity, improve biocompatibility, regulate their in vivo cycle, and introduce stress response functions (such as external Stimulation (light, heat, magnetism, etc.) response type and tumor microenvironment response type, etc.). For example, the researchers used hollow mesoporous silica in combination with a thermosensitive polymer to form a stable and thermally responsive hybrid nanocarrier. First, the researchers used magnetic iron oxide as template particles, cetyltrimethylammonium bromide as a pore-forming agent, hydrolyzed with tetraethyl orthosilicate to form silica nanoparticles, and used hydrochloric acid to remove stencil particles and pore formers. Hollow mesoporous silica. Second, the researchers added the precursor of Gd 2 O 3 : Eu 3+ to the hollow mesoporous silica and crystallized the Gd 2 O 3 :Eu 3+ fluorescent nanoparticles in the hollow cavity by calcination for optics. Imaging. Again, the researchers injected macromolecules into the hollow cavity and used photopolymerization to obtain a thermosensitive polymer in the cavity to form an organic-inorganic hybrid nanocarrier. The researchers loaded the drug indomethacin into the organic-inorganic hybrid nanocarrier, which not only obtained a stable system of drug treatment, prevented drug leakage, but also introduced a thermal response function to achieve controlled release of the drug. At the same time, Gd 2 O 3 : Eu 3+ is caused after drug release.Fluorescence recovery (fluorescence quenches when the drug is not released) can be used for real-time monitoring of the drug release process, helping to provide a personalized treatment regimen.
Challenge and outlook
As an emerging technology, the integration of cancer diagnosis and treatment has significant advantages in improving the therapeutic effect of cancer and reducing side effects. It is expected to promote the rapid development of cancer diagnosis and treatment technology and contribute to the early resolution of cancer. Of course, there are still many problems to be solved.
First, how to improve the specific uptake of nanomedicine in tumor tissue? In order to improve the specific uptake of nano-diagnostic agents by tumor tissues, on the one hand, it is necessary to optimize the targeting of nano-diagnostic agents, and use various specific targeting molecules or proteins to enhance the targeting effect of nano-diagnostic agents on tumor sites. On the other hand, it is necessary to improve the permeability of nanomedicines in tumor tissues. Since the tumor is composed of multiple layers of cells, it is difficult for the diagnostic agent to reach the central part of the tumor, and thus it is usually distributed stepwise from the center of the tumor to the periphery. In order to distribute the therapeutic agent evenly in the tumor tissue, it is necessary to improve the ability of the nanomedicine to penetrate various cell membrane structures. At present, one means to modify the transmembrane peptide with strong membrane-penetrating ability on the surface of nanomaterials. Another method is to construct a “viral-like nanomaterial” to improve its transmembrane ability. At the same time, for specific tumors, it is also necessary to improve the ability of nanomedicines to penetrate various biological barriers. For example, in order to use a nano-diagnostic agent for the treatment of brain tumors, it is necessary to overcome the blood-brain barrier and allow the nanomaterial to reach the tumor tissue of the brain. Therefore, the development of surface modification methods with breakthroughs in various biological barriers is crucial for the development of new nanomedicines.
Second, how to improve the diagnostic and therapeutic performance of nanomedicines? A large number of previous studies have shown that the single treatment method is often limited in the treatment of tumors, while synergistic treatment can achieve the effect of “1+1>2”. The use of synergistic therapy can overcome the tolerance of tumors to monotherapy. At the same time, studies have shown that in the synergistic treatment, nanomaterials have a better enrichment effect at the tumor site, which is also beneficial to improve the therapeutic effect of the therapeutic agent. For imaging, multimodal imaging often overcomes the false positives that monomodal imaging can bring, improving imaging and detection accuracy. Moreover, various imaging modes have their own advantages and scope of application. For example, X-ray imaging has a good effect on bone structure imaging, while nuclear magnetic imaging has a good effect on soft tissue imaging. Therefore, the use of multi-modal imaging can achieve complementary advantages and achieve better imaging results.
The integration of cancer diagnosis and treatment has developed rapidly in the last 10 years, but it also faces many challenges, especially in clinical transformation. In order to promote the development of cancer diagnosis and treatment integration, it is necessary to bring together the joint efforts of researchers in various fields, especially interdisciplinary cooperation in the fields of chemistry, materials and medicine. With the development of materials technology, nanomedicine and bioengineering, the integration of cancer diagnosis and treatment will provide a new opportunity for humans to overcome cancer.