Chen Peng research group of Peking University and Gao Yuan research group of national Nano Science Center have realized tumor targeting activation of biorthogonal prodrugs

Although the use of chemotherapy drugs is one of the main means of anti-tumor treatment at present, its side effects greatly limit the dosage, and often lead to tumor recurrence Tumor selective prodrug strategy can specifically activate and release drugs in tumor targeted areas, and has outstanding advantages in improving physicochemical, biological and pharmacokinetic properties of drugs, reducing the toxic and side effects of chemotherapy drugs Compared with the active targeting strategy represented by macromolecular antibodies and the passive targeting strategy represented by nanoparticles, using the microenvironment characteristics of tumor overexpression, such as enzymes, reactive oxygen species, hydrogen sulfide, etc., it is a new targeting mode to construct supramolecular assembly in situ by small molecule drug delivery, which has unique advantages in delivery efficiency, biological safety, etc Recently, Chen Peng research group of School of chemistry and molecular engineering of Peking University and Gao Yuan research group of National Center for nanoscience cooperated to realize in-situ and specific prodrug activation in tumor cells by enzyme triggered supramolecular self-assembly and biorthogonal bond breaking reaction, which not only greatly reduced the toxic and side effects of anticancer drugs, but also enhanced the targeted activation ability The related achievements were published in nature communications (DOI: 10.1038 / s41467-018-07490-6) under the title of "synergetic and biological reactions for selective prodrug activation in living systems" In this work, we designed and synthesized the enzyme response assembly precursor short peptide with the prodrug activation switch tetrazine Using the overexpressed phosphatase of cervical cancer cells, we constructed the functional nano assembly in situ in the tumor to make the prodrug activation switch achieve tumor targeting and a large amount of enrichment Tco-dox, a pre adriamycin drug, is not activated in normal cells or tissues and does not produce toxicity However, it can be effectively activated in tumors, which significantly improves the killing effect of cancer cells This work achieved tumor targeting by enzyme triggered supramolecular self-assembly, realized spatiotemporal controllable prodrug activation in cooperation with biorthogonal bond breaking reaction, constructed a safe and effective tumor inhibition strategy, and provided a new idea for expanding the treatment window of chemotherapy drugs In HeLa cells of cervical cancer, due to the over expression of phosphatase, when the current body concentration is higher than the critical assembly concentration, supramolecular self-assembly occurs in the precursor, which makes the precursor activation switch tetrazine molecules can be specifically enriched in tumor cells However, the phosphatase level of HUVECs in normal cells was low, so there was no self-assembly and tetrazine enrichment Therefore, we can target tumor cells by enzyme triggered supramolecular self-assembly, which lays a foundation for further specific activation of prodrug in tumor cells Animal model study further proved that tetrazine switch can selectively accumulate in tumor tissue and release doxorubicin before specific activation, making the concentration of doxorubicin in tumor tissue significantly higher than that in normal tissues such as liver The experimental results of tumor treatment show that the synergistic effect of self-assembly and biorthogonal reaction can significantly inhibit tumor growth, and has good biological safety Chen Peng's research group is the first to propose and develop biorthogonal cleavage reactions in the world, and relevant research has been at the international leading level Gaoyuan research group has long been committed to the research of supramolecular self-assembly system under physiological conditions and its application in the field of tumor diagnosis and treatment The above work was mainly completed by Yao Qingxin, postdoctoral student of Gaoyuan research group, Lin Feng, graduate student of Chen Peng research group, etc and was supported by national key research and development plan, National Natural Science Foundation and other projects and Peking University Tsinghua Life Science Joint Center.