Team of academician Tan Weihong of Hunan University: Design of new aptamer micelles to improve chemokinetic therapy of tumor

CDT is a new type of cancer treatment Compared with the traditional chemotherapy and radiotherapy, CDT can specifically respond to tumor microenvironment to produce toxic free radicals and induce tumor cell apoptosis Therefore, this method has been widely concerned by researchers At present, researchers have developed a large number of CDT therapies In essence, these methods mainly rely on the classical Fenton or Haber Weiss reaction, through the transition metal, the low toxic H 2O 2 and its analogues in tumor tissue are transformed into the highly toxic hydroxyl radicals (• oh) and other highly oxidative active substances However, high efficient Fenton or Haber Weiss chemical reaction requires strong acid environment (pH 2-4), while weak acid environment of tumor makes it difficult to be fully utilized In addition, the level of hydrogen peroxide in the tumor is obviously different, and it is consumed gradually with the reaction, resulting in a very limited content of toxic free radicals What's worse, cancer cells themselves adjust to oxidative damage caused by free radicals by up regulating antioxidant defense mechanism, which greatly reduces the effectiveness of this treatment How to make full use of the advantages of CDT therapy through ingenious system design is still facing great challenges Recently, academician Tan Weihong of Hunan University and Professor Liu Yanlan's team have made important progress in the field of CDT research, and put forward a new concept of CDT therapy of "combination of biorthogonal chemistry and prodrug" A new aptamer drug coupling compound (APDC): aptamer prodrug coupling compound (appdc) micelle was designed and synthesized It is worth noting that, unlike the traditional CDT therapy, this method does not depend on the strong acid environment and the content of H 2O 2, and can specifically identify cancer cells, and trigger a series of biorthogonal reactions under the activation of glutathione (GSH) inherent in cancer cells, in situ and self circulation to produce carbon center free radicals At the same time, the activation of prodrug can significantly reduce the content of GSH in cancer cells, increase the content of free divalent iron in cells, and produce a synergistic CDT effect This work provides new insights for the design of cancer targeted therapy and the study of free radical related molecular mechanisms At the same time, by changing the sequence of aptamers, the design is expected to prepare a series of targeted anticancer drugs for the efficient and selective treatment of a variety of malignant tumors (J am Chem SOC., 2019, DOI: 10.1021 / JACS 9b10755) Brief introduction to the team of academician Tan Weihong the molecular science and biomedical laboratory (MBL) of Hunan University was formally established in 2010, with Academician Tan Weihong of Chinese Academy of Sciences as the academic leader It is a new interdisciplinary research institution On the basis of chemistry, taking advantage of the research advantages of the State Key Laboratory of chemical biosensor and metrology, combined with its own research advantages in the fields of molecular science, material science, biology and nanotechnology, the laboratory designs and synthesizes new molecular tools for the difficult and frontier research of molecular medicine, striving to provide a basis for the further development of molecular medicine and translational medicine A revolutionary platform for scientific research and technological exchange The main research fields of the team include chemical biology, life analysis chemistry, functional materials and nano science, molecular medicine, etc The specific research contents include: developing new methods and technologies of chemical biosensor, designing and developing new functional nanomaterials and molecular probes; carrying out basic and applied research of molecular medicine, realizing high sensitive detection and early diagnosis of biological molecules related to major diseases; integrating molecular biology, genomics and Proteomics technology, to build a multi-disciplinary cross research platform, to find the early diagnosis, treatment and prognosis of malignant tumors have guiding significance of molecular markers and molecular targets; to promote the close combination of basic research and clinical application, to provide revolutionary molecular tools for transformation medicine and personalized medicine In recent years, the team has made breakthroughs in the field of aptamer, bioanalytical chemistry and chemical biology based on aptamer The team took the lead in the world in putting forward the new concept of aptamer living cell screening, establishing the aptamer screening method with living cells as the target, and using the obtained molecular probes to achieve the specific recognition of cancer and other major disease cells, It has opened up a new way to solve the problem of lack of molecular probes in cell analytical chemistry, and proposed a series of new principles of aptamer analytical chemistry: using aptamer to discover disease-related proteins of leukemia and other cancers, measuring the structural parameters of these proteins, establishing a new method of quantitative analysis and optical imaging of these proteins, and systematically studying the molecular bases recognized by aptamer cells A new direction of cross research between nanomateriation and analytical chemistry was explored: new biomaterials, such as DNA micelles and DNA hydrogels, were developed, and a new strategy of signal amplification was constructed based on nucleic acid molecular engineering A new targeted drug delivery system based on nucleic acid was developed, which provided an important molecular tool and platform for diagnosis and treatment of major diseases About academician Tan Weihong, doctor of physical chemistry, University of Michigan, master of physical chemistry, Chinese Academy of Sciences, Bachelor of chemistry, Hunan Normal University At present, he is the director of Institute of oncology and basic medicine, Chinese Academy of Sciences, and professor of Cancer Hospital Affiliated to Chinese Academy of Sciences He also serves as the dean of the Molecular Medicine Research Institute of Shanghai Jiaotong University and a professor of the school of chemistry and chemical engineering and the school of biology of Hunan University Professor Tan Weihong's main research fields are biological analytical chemistry, chemical biology and molecular medicine He has published more than 650 academic papers, h-index 136, and cited nearly 64000 times in well-known international and domestic academic journals From 2014 to 2019, he was selected into the global list of highly cited researchers by Thomson Reuters for six consecutive years The research achievements won the first prize of natural science of the Ministry of education in 2011, the Florida prize of American Chemical Society in 2012, the second prize of National Natural Science in 2014, the "spectrochemical analysis Award" of American Chemical Society in 2018, the science and technology award of Ho Liang Ho Li foundation in 2018, the Pittsburgh analytical chemistry achievement award in 2019, and the outstanding contribution award of biological analytical chemistry in 2019 In 2005, he was elected AAAs fellow of the United States, academician of the Chinese Academy of Sciences in 2015, and academician of the Academy of Sciences in developing countries in 2016 Prof Liu Yanlan, State Key Laboratory of chemical biosensor and metrology, Professor of School of chemistry and chemical engineering, Hunan University, laboratory of molecular science and biomedicine, doctoral supervisor, and winner of "Youth Program" of national thousand talents plan Mainly engaged in the design and synthesis of multi-functional imaging probes, in vivo imaging and molecular targeted intervention in major diseases such as cancer and cardiovascular and cerebrovascular diseases The related work was published as the first author and corresponding author in international authoritative journals such as chem Rev., acc chem Res., PNAs, J am Chem SOC., angel Chem Int ed., adv mater The research results were reported by Science Translational Medicine, nanowerk and other special topics The total number of citations is more than 5000 Multiple articles are included in "ESI highly cited articles" Advanced scientific research achievements: the design of new aptamer micelles and the improvement of tumor chemokinetic treatment Figure 1 The schematic diagram of biorthogonal appdc micelles in situ and amplification to produce toxic free radicals in cancer cells (source: J Am Chem Soc.) first, the authors used phosphite amide chemistry and DNA solid-phase synthesis technology to introduce different quantities of "T" at the 5 'end of aptamer, and confirmed by gel electrophoresis analysis and atomic force microscopy (AFM) analysis, the uniform and monodisperse spherical structure (e.g Ap-6G- "T" average size of 32.4) was confirmed Nm) Dynamic light scattering (DLS) and Z potential measurements further showed that the micelles were stable and negatively charged under physiological conditions, without obvious aggregation, and had very good serum tolerance and nuclease stability Fig 2 Synthesis diagram of prodrug "t"; and its characterization (source: J am Chem SOC.) on the study of activation mechanism, the author first used small molecules to react with free Fe2 + or hemin Through free radical capture experiment and mass spectrometry analysis, it is preliminarily proved that prodrug can be activated by Fe2 + source and produce free radicals In the subsequent cell experiments, the author first investigated the targeting of this kind of appdcs on HepG2 cells Compared with the non targeting micelles, the uptake of appdcs micelles increased significantly, resulting in more toxic free radicals, which had a significant anti value-added effect on cells With the increase of the number of prodrug "t", the anticancer effect is enhanced Under the same conditions, the cytotoxicity of the prodrug is reduced from 50 μ m to 4.79 μ m (ap-6g-h-2 "t"), which further confirms the importance of micelles formed by aptamers in targeted delivery and improving bioavailability Fig 3 Activation mechanism of prodrug base "t" mediated by free Fe2 + or heme (Fe2 +) (source: j.am Chem SOC.) Fig 4 Antitumor effect of appdcs micelles (source: j.am Chem SOC.) Summary: the author proposed a new concept of "combination of biorthogonal chemistry and prodrug" for CDT therapy The new aptamer drug coupling compound (APDC): aptamer prodrug coupling compound (appdc) micelle was successfully used to target HepG2 It can produce free radicals in a cyclic way without depending on the strong acid environment and the content of H 2O 2, and consume glutathione (GSH) and reduce oxidative stress This kind of prodrug "base" can be introduced into any sequence of nucleic acid aptamers by the way of solid-phase synthesizer Therefore, it is expected to prepare a series of targeted anticancer drugs for the efficient and selective treatment of a variety of malignant tumors The work "molecular self assembly of biological aptamer prodrug reconcile cells for hydrogen peroxide and pH independent cancer chemodynamic theory" was published in J am Chem SOC (2019, DOI: 10.1021 / JACS 9b10755) The first author is Dr Xuan Wenjing and Xia Yinghao from Hunan University The corresponding authors are academician Tan Weihong and Professor Liu Yanlan of Hunan University (thesis authors: Wenjing Xuan, Yinghao Xia, Ting Li, Linlin Wang, Yanlan Liu, and Weihong tan) Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.