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The visible imaging technique of living animals can observe the changes of tumor cells after administration, mainly whether the tumor cells die or not, and whether the tumor volume becomes smaller. The most appropriate drug delivery strategy is designed by the specific route of administration, time, dose, and changes in tumor cells. In other words, efforts are made to improve the bioavailability of the drug, the stable blood drug concentration, the excellent drug metabolism parameters, and the targeting of the drug, and finally achieve the therapeutic effect with the minimum dose of administration, so as to avoid Possible toxic side effects. The photon value obtained by visible imaging of living animals is linearly related to the volume of tumor cells. Although it is functional imaging, it only plays the role of structural imaging for observing the effect of tumor antitumor drugs. How much and how much the tumor cells change. As long as the cells are alive, they can be observed, regardless of the living state and metabolic capacity of the cells, and the degree of activity. The metabolic changes that the tumor cells first display after drug treatment are not available. Moreover, due to the diffuse nature of visible light in the living body, the resolution of living bioluminescence is very low, about 3-5 mm; the resolution of living fluorescent imaging can only reach 2-3 mm when using a 4 megapixel CCD. Achieve the requirements for precise positioning. In addition, due to the attenuation of visible light in the living body, the results obtained cannot be absolutely quantified, and these objective reality require the application and development of other imaging modes.
Small animal PET or SPECT technology can not only observe the volume change of the tumor, but also observe the metabolic changes of the tumor cells early. When the tumor cells are alive, the metabolism of glucose, choline and amino acids can be observed. This technology is a true functional imaging that allows for the observation of metabolic changes before cell death. Some researchers have used 11C-labeled choline as a tracer to observe human prostate cancer animal models, and found that the tumor/muscle ratios in C4-2, PC-3, CWR22rv and LNCaP are different. Metabolic information of tumor biological processes. In addition, the technology can obtain three-dimensional tomographic information, which can accurately calculate the volume of the tumor with a resolution of 1.8 mm. Most importantly, the technology can observe the ADME of the drug, study the specific target of the drug, and obtain dynamic information. Although small animal PET technology has not yet been popularized, it is foreseeable that in the near future, it will be an indispensable technology for new drug research.
Before you use the small animal visible light imaging technology to understand how much the cells change after the tumor is treated by the drug, is it also concerned that the drug works through the link, and does the drug have to pass a specific biomarker to function? What is the metabolic pathway of drugs in the body? Does the drug reach the tumor cells? Does the metabolic activity of the tumor cells change before the death of the tumor cells, that is, whether the amino acid metabolism, glucose metabolism, and choline metabolism of the tumor cells are abnormal? This series of questions is understood through small animal PET technology. The NightOWL IILB 983 live animal optical imaging system combined with the small animal PET imaging system is the perfect solution to the above scientific research problems, providing a comprehensive solution from bioluminescence, reflected fluorescence, transmission fluorescence to PET (including SPECT) imaging, ie through the tumor The volume reduction can understand the effect of anti-tumor drugs, and the metabolic changes of tumor cells after administration can be observed in advance, and the target of the drug action can be understood by the tracing of the positron-labeled drug (especially Asians, Chinese specific targets), can also understand the ADME process of the drug in the human body.
In summary, when you purchase a small animal visible light imaging system, do you consider future development and compatibility as one of the considerations, so that you will be the leader in the field of molecular imaging technology for drug research, without worrying about the future. The bioluminescence or fluorescence imaging data is compatible with PET imaging results, and Berthold's instrument designers have made long-term considerations for you. The combination of the two different imaging principles of the NightOWL IILB 983 live animal optical imaging system and the small animal PET imaging system is not a simple addition of its functions, but based on this, the image fusion through the unified animal bed MACU means that The images of the same or different imaging modes are matched by a certain transformation process to match their spatial and spatial coordinates. The image fusion processing system uses the characteristics of the respective imaging modes to spatially register and combine the two images, and then register and synthesize the image data. For a single image.
I. Application of live animal optical imaging technology in pharmacodynamic research
The tumor cells labeled with the luciferase gene or the GFP/RFP gene are subcutaneously inoculated into the mouse to cause a subcutaneous tumor model, and after the administration of a specific drug, the growth and changes of the tumor cells are observed. The advantage of labeling by GFP/RFP gene is that the substrate fluorescein is not required and does not require a long detection time, but is not suitable for in situ vaccination. The advantage of labeling with the luciferase gene is that in situ vaccination can be performed, but the detection time is longer and the substrate fluorescein is required. However, when studying the therapeutic effects of antitumor drugs, there are usually more subcutaneous models.
Fluorescence imaging
Researchers at the Cancer Institute of Jiaotong University applied the NightOWL IILB 983 live animal optical imaging system to establish an experimental model of mouse lung cancer through the H-460-GFP subcutaneous tumor model, which can be used to screen anticancer drugs. The subject has been applied for funding from the Shanghai Science and Technology Commission and plans to establish a live model of 3-5 tumors for drug screening.
2. Bioluminescence imaging
Antitumor efficacy of antitumor drug Topotecan. It was observed by a tumor model inoculated subcutaneously. At present, the author has not found a report on the therapeutic effect of drugs by in situ vaccination.
3. Small animal PET can detect changes in tumor metabolism
Metabolic imaging of tumors using small animal PET technology, including glucose, amino acids, lipids, choline metabolism imaging, etc., to understand how the drug works, and to observe the occurrence and development of tumors by glucose metabolism imaging. Commonly used. The researchers studied the anti-prostate cancer drug treatment by injecting CWR22 prostate cancer cells into mice by PET imaging. The tumor volume was not significantly reduced on the fourth day, but the absorption of FDG has decreased by 43%. . This finds the therapeutic effect of the drug earlier than the visible imaging of living animals, and can find the therapeutic mechanism. It indicates that the tumor cells first metabolized abnormally before death, and then died.
Researchers at the University of Milan applied a small animal PET imaging system to label glucose, choline, etc., and observed the metabolism of the above substances in tumor cells, and achieved good results. The use of small animal PET for tumor metastasis imaging is still in its infancy and there are many unexplored areas. I believe that with the popularity of this technology, there will be many new discoveries.
Second, the impact of drugs on gene expression
According to the research purpose, the researcher will label the target gene with luciferase and transfer it into the animal to form the desired disease model, including tumor, immune system disease, infectious disease, etc., which can provide real-time expression and target of the target gene in vivo. Accurate responses to drug candidates can also be used to assess the toxicity of drug candidates and other compounds, providing a means of research for the mechanism and utility of drugs in disease. Researchers at the Shanghai Southern Model Animal Center used the NightOWL IILB 983 live animal optical imaging system to observe the induction of specific gene expression or closure by Chinese medicine. The IL-1β gene was labeled with a luciferase gene to form a transgenic mouse, and the IL-1β gene was expressed in parallel with the luciferase gene. By constructing such a platform to screen for inflammation-related therapeutic drugs, it will be a pioneer in the application of live animal optical imaging technology in the field of Chinese medicine, and will greatly promote the development of Chinese medicine research methodology. The subject was funded by the Shanghai Science and Technology Commission and relevant literature has been published.
Third, drug ADME research
Labeling drugs with fluorescent dyes allows for in vivo distribution and targeting studies of drugs, but because of the limited types of fluorescent dye-labeled drugs that cannot be imaged dynamically, small animal PET remains the primary technology for preclinical ADME studies of drugs. Researchers at the Cancer Institute of Jiaotong University used Cy5.5-labeled antibodies for in vivo metabolism experiments, showing the distribution of labeled antibodies in the liver, kidney, etc. This is the fluorescent labeling drug in vivo targeted research application NightOWL IILB 983 living body A precedent for animal optical imaging systems. Researchers at Fudan University of Pharmacy also used quantum dot-labeled drugs to observe the targeting of drugs in the brain, and related experiments are underway. These experiments extend the application of fluorescence imaging. The depth of detection is not limited to the surface of the mouse, and the images obtained are clear, without strong interference from the background light, which will greatly facilitate the field of pharmacy. The application of imaging technology.
Small animal PET can obtain detailed pharmacokinetic information of radiolabeled drugs or similar drugs, ie information on ADME (absorption, distribution, metabolism, excretion) of drugs. That is, the technique can observe whether the drug crosses the blood-brain barrier, whether there is organ-specific aggregation, whether the target receptor is recognized, and the ratio of drug content in plasma to tissue. In short, the small animal PET technology can monitor the whole process of drug action, provide vital information, and compare the condition of the animal disease model before and after treatment. It can also know the possible tissue damage and conduct a comparative study between human and animal. For example, an Italian researcher used the 11C-labeled compound PK11195, VC701, to inject into rats and observe the distribution pattern caused by the recognition of PBR receptor. After competitive blocking by antagonist PK11195, 11C- The binding of VC701 to the receptor is significantly reduced. Small animal PET can show whether a drug binds to a specific molecular target. PET imaging can determine the drug's transport in the body and bind to the target tissue and its pharmacokinetics in vivo. It can non-invasively evaluate the inhibitory effect of the drug on other biological sites, and can be used to optimize the therapeutic dose for tumor patients.
Application of combined application of living animal molecular imaging technology in new drug research
The emerging molecular imaging technology has attracted the interest of many researchers in the field of new drug research. At all stages of new drug research, molecular imaging technology has increasingly demonstrated its superiority and indispensability, playing an increasingly important role. . Molecular imaging technologies include live animal visible light imaging technology, small animal PET (SPECT) technology, and small animal CT technology. The visible imaging technology of living animals is the first to be popular because of its simple operation and relatively low price. With the development of molecular imaging technology, small animal PET technology will gradually overcome the price threshold of radiochemistry and the price threshold of instruments due to its advantages in drug metabolism, etc., and will gradually become an indispensable technology in drug research. According to the current application data, we can conclude that living animal visible light imaging technology and small animal PET technology will become the two most important technologies in new drug research. So how are these technologies applied in new drug research? What are the advantages and disadvantages of each, this is the question to be answered in this article.