Dually Enzyme- and Acid-Triggered Self-Immolative Ketal Glycoside Nanoparticles for Effective Cancer Prodrug Monotherapy

Yu, N (Yu, Na)^{[ 1 ]} ; Liu, T (Liu, Tao)^{[ 1 ]} ; Zhang, X (Zhang, Xi)^{[ 1 ]} ; Gong, NQ (Gong, Ningqiang)^{[ 2,3 ]} ; Ji, TJ (Ji, Tianjiao)^{[ 4 ]} ; Chen, J (Chen, Jing)^{[ 2,3 ]} ; Liang, XJ (Liang, Xing-Jie)^{[ 2,3,5 ]} ; Kohane, DS (Kohane, Daniel S.)^{[ 4 ]} ; Guo, ST (Guo, Shutao)^{[ 1 ]}

NANO LETTERS, 2020, 20(7): 5465-5472

DOI: 10.1021/acs.nanolett.0c01973

摘要

The use of glycoside prodrugs is a promising strategy for developing new targeted medicines for chemotherapy. However, the in vivo utility of such prodrugs is hindered by insufficient activation and the lack of convenient synthetic methods. We have developed an innovative strategy for synthesizing ketal glycoside prodrugs that are unique in being activated by a dual enzyme- and acid-triggered self-immolative mechanism. Amphiphilic glucosyl acetone-based ketal-linked etoposide glycoside prodrug isomers were synthesized and fabricated into excipient-free nanoparticles for effective cancer prodrug monotherapy. Hydrolysis of the glycosidic linkage or the ketal linkage triggered hydrolysis of the other linkage, which resulted in spontaneous self-immolative hydrolysis of the prodrugs. Nanoparticles of the prodrug isomer that was the most labile in a lysosome-mimicking environment displayed high intratumoral accumulation and strong antitumor activity in an A549 xenograft mouse model. Our strategy may be useful for the development of stimulus-responsive self-immolative prodrugs and their nanomedicines.