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 of cancer cells was not reported. Herein, a pyrene-peptide conjugate Py-Phe-Phe-Glu-Tyr(H2 PO3 )-Gly-lyso (Py-Yp-Lyso) is rationally designed and demonstrated for 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 is efficiently dephosphorylated by ALP to yield Py-Phe-Phe-Glu-Tyr-Gly-lyso (Py-Y-Lyso) which self-assembles into nanofibers. Cell experiments verified that, after being taken up by HeLa cells, the excimer fluorescence of Py-Yp-Lyso assemblies has turned "on" and the assemblies specifically target the lysosomes, inducing LMP and ultimate cancer cell death. In vivo experiments indicated that Py-Yp-Lyso has the highest inhibition effect on HeLa tumors among the four compounds studied. This is anticipated for applying Py-Yp-Lyso to treat cancers in the clinic in the future.