Science Frontier

Li Zifu and Yang Xiangliang's teams develop a novel antitumor prodrug and its nanoformulation

Oct 20, 2021

On October 9, Professor Li Zifu, Professor Yang Xiangliang and their team members from the School of Life Science and Technology and the National Engineering Research Center for Nanomedicine published a research paper entitled “A novel prodrug and its nanoformulation suppress cancer stem cells by inducing immunogenic cell death and inhibiting indoleamine 2, 3-dioxygenase” in the authoritative journal Biomaterials (IF=12.479), proposing a new strategy to eliminate cancer stem cells (CSCs) by regulating CSCs niche. Based on this strategy, a novel antitumor prodrug and its nanoformulation were designed and developed.

Malignant tumors have become the first cause of death in China, presenting a great threat to national health. One of the key obstacles hindering the treatment of malignant tumors is CSCs. Clinical data indicate that there are abundant CSCs in most tumors. Chemotherapeutic drugs are currently the main means of treating various tumors. However, traditional chemotherapeutic drugs not only cannot effectively kill CSCs, but also increase the proportion of CSCs and lead CSCs into dormancy, reducing their response to drugs and immune cells. Besides, the immunosuppressive microenvironment of tumors creates a favorable CSC niche suitable for CSC growth and proliferation with immune cells, cytokines, and amino acids. How to effectively eliminate CSCs became an urgent issue in clinical tumor treatment.

Based on the background hereinbefore, this study proposes a new strategy to eliminate CSCs by regulating CSCs niche. On the one hand, the strategy uses chemotherapeutic drugs to induce immunogenic cell death (ICD), promote DC maturation and enhance the antitumor immune responses. On the other hand, the strategy inhibits indoleamine-2,3-dioxygenase (IDO) to regulate immune cells, cytokines, amino acids, etc. Therefore, the CSCs niche will be converted to a hostile condition for CSCs to live and the CSCs dormancy will be relieved. The sensitivity of CSCs to chemotherapeutic drugs and immune cells will be enhanced, effectively killing CSCs and tumor cells. As a result, the therapeutic effect of cancer is supposed to be improved. Based on this strategy, a novel antitumor prodrug and its nanoformulation have been successfully designed and developed. Its antitumor efficacy in the triple-negative breast cancer (TNBC) model is significantly better than the clinical first-line drugs Paclitaxel and Irinotecan.

This study is of great guiding significance for the research on CSCs elimination. To eliminate CSCs, this study combines immunogenic cell death and IDO inhibition to improve the CSCs niche and relieve CSCs dormancy. This study systematically evaluated the antitumor activity, toxicity, and optimal dosage of the prodrug CN and its nanoformulation. The prodrug CN and its nanoformulation have been patented by the China National Intellectual Property Administration with a good prospect of clinical transformation.

Guan Jiankun (doctoral student), Wu Yuxin (postgraduate student), and Dr. Liu Xin (postdoctoral fellow) from the School of Life Science and Technology are the co-first authors of the paper.

Editor:Lu Yizhong,Peng Yumeng

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