Enzymatic Nanosphere‐to‐Nanofiber Transition and Autophagy Inducer Release Promote Tumor Chemotherapy. Issue 23 (9th October 2022)

• Record Type: Journal Article
• Authors: Cheng, Xiaotong; Xia, Tiantian; Zhan, Wenjun; Xu, Hai‐Dong; Jiang, Jiaoming; Liu, Xiaoyang; Sun, Xianbao; Wu, Fu‐Gen; Liang, Gaolin
• Is Part Of: Advanced healthcare materials. Volume 11:Issue 23(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-09
• Subjects: autophagy -- cancer -- morphology transformation -- self‐assembly -- tandem enzyme‐responsiveness; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/adhm.202201916
• Languages: English
• ISSNs: 2192-2640

Abstract

Abstract: Chemotherapy has remained an effective and predominant cancer treatment for the past decades, but is hampered by its low response rate and severe systemic toxicity. Combination chemotherapies are proposed to address these issues, yet their therapeutic outcomes are still far from satisfactory. Thus, it is urgent to develop novel strategies to promote tumor chemosensitivity while reducing toxic side effects of chemotherapeutics. Herein, employing a rationally designed peptide conjugate Nap‐Phe‐Phe‐Lys(SA‐AZD8055)‐Tyr(H2 PO3 )‐OH (Nap‐AZD‐Yp ), a novel approach of simultaneous intracellular nanofiber formation and autophagy inducer release is proposed for selectively sensitizing tumor to chemotherapy. Upon sequential catalyses of alkaline phosphatase and carboxylesterase, Nap‐AZD‐Yp undergoes nanosphere‐to‐nanofiber transition accompanied by autophagy inducer AZD8055 release in cancer cells. Cell experiments show enhanced endocytosis of anticancer drug doxorubicin and inhibition of cell migration due to the intracellular nanofiber formation. The released AZD8055 further activates excessive autophagy of cancer cells, sensitizing them to chemotherapy. Animal experiment results suggest Nap‐AZD‐Yp can significantly enhance the therapeutic effects of doxorubicin on tumors while mitigate its toxic adverse effects on normal tissues. It is anticipated that the "smart" concept in this work c be widely employed to develop novel combinational therapies for the treatment of cancers and other diseases in near future. Abstract : A peptide conjugate Nap‐Phe‐Phe‐Lys(SA‐AZD8055)‐Tyr(H2 PO3 )‐OH (Nap‐AZD‐Yp ) is designed to promote tumor chemosensitivity. Upon sequential alkaline phosphatase dephosphorylation and carboxylesterase hydrolysis, nanospheres of Nap‐AZD‐Yp are converted into nanofibers, accompanied by the release of AZD8055 in cancer cells. The nanofiber formation promotes endocytosis of chemotherapeutics, and AZD8055 release activates excessive autophagy, which synergistically lead to enhanced apoptosis of cancer cells.