Chen, academician Tang benzhong and Professor Ding Dan: intramolecular motion promotes fluorescence photoacoustic Raman imaging and is used for precise surgical navigation

Accurate tumor imaging plays an important role in the success of cancer surgery For cancer patients, removal of all tumor lesions is the key to completely cure cancer and prolong life However, the existing imaging technology can not meet the requirements of different stages of tumor resection at the same time For example, although fluorescence imaging technology has high sensitivity, its penetration depth and spatial resolution are poor; photoacoustic imaging technology can provide better penetration depth and high spatial resolution, but its sensitivity is not high; although Raman imaging is not as sensitive as fluorescence imaging, and there are many spectral peaks, but in the cell silence area (1800-2800 cm-1 ）It can realize the detection of high signal-to-noise ratio and zero background interference, which is very effective for the detection of living tissue Therefore, how to integrate the advantages of fluorescence, photoacoustic and Raman imaging technology to achieve accurate imaging of the focus area is the key to improve the success rate of tumor surgery At present, the commonly used method to prepare multimodal imaging reagents is to combine different reagents in one system, that is, to combine multiple components with different functions (all in one), so as to play their respective roles Although the strategy is effective, it is faced with complex composition and poor repeatability, which limits its clinical transformation Another strategy is that a single molecule has multiple properties at the same time (one for all) This probe has simple components, clear structure, good repeatability and better clinical transformation prospects However, it is very difficult to design and optimize the probe For example, fluorescence, photoacoustic and Raman imaging correspond to different photophysical processes At the same time, optimizing these properties is very challenging, so there are few reports Recently, academician Tang benzhong of Hong Kong University of science and technology and Professor Ding Dan of Nankai University jointly reported for the first time that a single molecule can produce three kinds of signals (one for all), namely fluorescence, photoacoustic and Raman By adjusting the molecular structure and intramolecular movement, these three properties can be optimized at the same time And it can be used for navigation in different stages of operation, which greatly improves the success rate and survival rate of tumor resection This work was recently published in the cell sister journal chem (if: 18.2, DOI: 10.1016 / j.checker 2019.07.015) Brief introduction to academician Tang benzhong, academician of the Chinese Academy of Sciences, Professor of science Zhang Jianquan, Department of chemistry and biomedical engineering, Hong Kong University of science and technology, Dean of the Joint Research Institute of South China University of technology and Hong Kong University of science and technology In 1982, he received his bachelor's degree from South China University of technology, master's degree and doctor's degree from Kyoto University of Japan in 1985 and 1988; he once worked in the Department of chemistry and pharmacy of the University of Toronto as a postdoctoral researcher and as a senior researcher in the Central Research Institute of Neos company of Japan; 1994 He has successively served as assistant professor, associate professor, Professor, Chair Professor and Zhang Jianquan professor of Science in the Department of chemistry of Hong Kong University of science and technology since 2012; he was elected as academician of the Chinese Academy of Sciences in 2009; he was elected as fellow of the Royal Society of chemistry in 2013; he has been employed as dual academician of South China University of technology since 2012; he has been the director of the Joint Laboratory of South China University of technology and Hong Kong University of science and technology since 2012; 2015 He has been the director of Hong Kong Branch of National Engineering Technology Research Center since He is now the chief scientist of the 973 Program of the Ministry of science and technology, the project director of the basic science research center of the National Natural Science Foundation of China, the leader of the introduction and innovation research team of Guangdong Province, the director of the academic committee of the State Key Laboratory of light emitting materials and devices of South China University of technology, and the editor in chief of materials chemistry frontiers, a joint Journal of the Chinese Chemical Society and the Royal chemical society Academician Tang benzhong has published more than 1200 academic papers, cited more than 85000 times in total, with an H-index of 135 He was successively selected as a high cited scientist in the fields of chemistry and materials in 2014-2018 At the same time, Professor Tang benzhong has won many honors and awards, such as the first National Natural Science Award (2017, the first adult), he Liang and he Li science and Technology Progress Award (2017), the 27th International Science Award (2014), polymer Academic Report Award of American Chemical Society (2012), and the second National Natural Science Award (2007) , the fourth adult), Qiu Cha advanced research achievement award (2007), Wang Baoren Award for polymer basic research of China Chemical Society (2007), Feng Xinde polymer award of Elsevier press (2007), etc Introduction to Professor Ding Dan, professor and doctoral supervisor of Key Laboratory of Ministry of education of bioactive materials, National Key Laboratory of pharmaceutical chemistry and biology, School of life sciences, Nankai University The research direction of the research group is the design, preparation and biomedical application of new molecular image probes The research group is mainly based on "aggregation induced luminescence" (AIE) fluorescent molecules and other organic polymers rich in intramolecular motion units, combined with biomedical polymer materials to design and prepare a new type of molecular image probe, to explore its biomedical application in the diagnosis and treatment of major diseases and the research on the mechanism of disease occurrence and development Ding Dan graduated from the Department of chemistry, Nanjing University in 2005, and from the Department of polymer, Nanjing University in 2010 with a doctorate in science, under the guidance of Professor Jiang Xiqun Later, he went to the research group of Professor Liu Bin of the Department of chemistry and Biomolecular Engineering of National University of Singapore to engage in postdoctoral work During this period, he completed the early exploration in the field of AIE biomedical materials under the guidance of Professor Liu Bin and academician Tang benzhong of Hong Kong University of Science and technology He joined Nankai University in January, and then went to the research group of academician Tang benzhong of Hong Kong University of science and technology for exchange and study Since joining Nankai University, Ding Dan has been selected into the "one hundred young subject leaders" and other training programs of Nankai University, and has been supported by the excellent young science fund program of the National Natural Science Foundation of China In the past five years, more than 40 papers have been published by communication / CO communication authors, half of which have been published in journals with impact factor > 10, and H factor is 41 Cutting edge research achievements: intramolecular motion promotes fluorescence photoacoustic Raman imaging and is used for precise surgical navigation The concept of aggregation induced luminescence (AIE) proposed by academician Tang benzhong has shown a good application prospect in biomedical imaging and treatment Its main idea is to regulate and utilize intramolecular motion In terms of luminescence, it is also expected to integrate the seemingly contradictory but related optical properties of molecules, such as fluorescence, photoacoustic and Raman, and maximize their biomedical applications Academician Tang benzhong and Professor Ding Dan cooperated to prepare one for all organic molecular probe with near-infrared fluorescence, photoacoustic and Raman signals at the same time Using the advantages of different imaging modes, applying the probe to different stages before and during surgery can effectively improve the effect of tumor surgery (Figure 1) The results show that the properties of fluorescence, photoacoustic and Raman can be optimized by adjusting the intramolecular motion, and the micro intramolecular motion can be organically combined with a variety of macro biological applications, which greatly expands the application potential of the concept of AIE in the biomedical field Fig 1 The team of fluorescence / photoacoustic imaging and intraoperative fluorescence / Raman imaging using organic molecular probes first synthesized three kinds of molecules with different substituents (Fig 2), and compared the photophysical properties and imaging results All of them have typical AIE properties, especially otpa-tq3 has the largest and most twisted substituents, so its fluorescence enhancement is the most obvious and has the highest fluorescence quantum yield By comparing the photoacoustic properties in different viscosity environments, it is found that with the decrease of the viscosity of the system, the movement ability of the molecules is enhanced, so the photoacoustic properties are also improved; further comparing the Raman signal strength in different aggregation states (organic solution, water-soluble nanoparticles and large aggregates), it is found that with the increase of the movement ability of the molecules, the Raman signal is also greatly enhanced (Fig 3) What's more interesting is that the effects of these properties are more obvious in the molecules with large substituents Therefore, otpa-tq3 with large volume substituents (phenyl alkynyl phenyl) shows the best optical imaging properties at the same time Figure 2 Molecular structure, optimal configuration and basic photophysical properties Figure 3 Photoacoustic and Raman properties in different motion states The fluorescence, photoacoustic and Raman signals all come from the excitation of external light sources The fluorescence and photoacoustic signals are related to the radiative and non radiative transitions of excited fluorescent molecules, respectively The Raman signals come from the vibrational relaxation of virtual energy levels The three processes are closely related to the molecular motion When the molecular motion becomes stronger, the photoacoustic and Raman signals are enhanced, and the fluorescence intensity is weakened Therefore, it is very difficult to promote the two competitive processes in the same organic molecule at the same time The excellent properties of organic molecular probes in this work are mainly attributed to the following aspects: 1 Significant AIE effect, which can effectively enhance the fluorescence intensity of the aggregation state; 2 Intramolecular movement of the excited state and high molar absorption coefficient lead to strong photoacoustic signal; 3 Conjugated "phenyl alkynyl" in the molecule- Phenyl "substituents and intramolecular movement can produce strong Raman signals in the silent region of cells Based on these characteristics, otpa-tq3 can produce strong fluorescence photoacoustic Raman signal at the same time, which has the potential for accurate tumor imaging Figure 4 Coating of organic molecular probes into nanoparticles and their properties Coating hydrophobic organic molecules into water-soluble nanoparticles with uniform size and morphology under the action of polymer surfactant (Figure 4), which has good biocompatibility and can be used for in vivo imaging The imaging performance and stability of the nanoprobe are better than many traditional organic / polymer materials, and it is suitable for long-term in vivo imaging The research team injected the otpa-tq3 nano probe with the best imaging effect into the tumor mice through the tail vein, and carried out the research in vivo imaging and tumor resection operation navigation Figure 5 Fluorescence and photoacoustic imaging of organic molecular probes before surgery Preoperative imaging requires high spatial resolution and high sensitivity to provide information such as tumor size, size, location, etc Therefore, these information can be obtained by using the high sensitivity of near-infrared fluorescence imaging and the high spatial resolution and tissue penetration of photoacoustic imaging (figure 5) Because of EPR effect, the nanoprobe can be well enriched in the tumor site and provide imaging results with high signal-to-noise ratio Under the guidance of fluorescence and photoacoustic imaging, the tumor was surgically removed In clinic, the challenge for surgeons is how to determine the residual micro tumor and the boundary between tumor and normal tissue after removing large tumor Small tumor remains are often the important cause of postoperative recurrence and metastasis Rapid, sensitive and accurate imaging methods are needed in the operation Therefore, the authors used rapid near-infrared fluorescence imaging to identify the residual micro tumors, and further verified the tumor tissue by Raman imaging (Fig 6) Because of the background interference in fluorescence imaging, it is impossible to accurately determine the tumor, while the "zero background" Raman imaging in the cell silence area can well confirm the tumor tissue Confirm residual tumor