Lysosome-Targeted and Fluorescence-Turned "On" Cytotoxicity Induced by Alkaline Phosphatase-Triggered Self-Assembly.

Selectively inducing lysosomal membrane permeabilization (LMP) is a promising strategy for cancer therapy. But integrating alkaline phosphatase (ALP)-instructed self-assembly and lysosome-targeting to induce LMP for selective killing cancer cells was not reported. Herein, we rationally designed a pyrene-peptide conjugate Py-Phe-Phe-Glu-Tyr(H2 PO3 )-Gly-lyso (Py-Yp-Lyso) and demonstrated its lysosome-targeting cytotoxicity on cancer cells, together with its pyrene (Py) excimer fluorescence turning "on" at 480 nm. In vitro results showed that, Py-Yp-Lyso was efficiently dephosphorylated by ALP to yield Py-Phe-Phe-Glu-Tyr-Gly-lyso (Py-Y-Lyso) which self-assembled into nanofibers. Cell experiments verified that, after taken up by HeLa cells, the excimer fluorescence of Py-Yp-Lyso assemblies was turned "on" and the assemblies specifically targeted the lysosomes, inducing LMP and ultimate cancer cell death. In vivo experiments indicated that Py-Yp-Lyso had the highest inhibition effect towards HeLa tumors among the four compounds studied. We anticipate to apply Py-Yp-Lyso to treat cancers in clinic in the future. This article is protected by copyright. All rights reserved.