Results
Title

A pH‐Driven Small‐Molecule Nanotransformer Hijacks Lysosomes and Overcomes Autophagy‐Induced Resistance in Cancer.

Authors

Ma, Zhao; Lin, Kai; Tang, Menghuan; Ramachandran, Mythili; Qiu, Reng; Li, Jin; Solano, Lucas N.; Huang, Yanyu; De Souza, Cristabelle; Abou‐Adas, Sara; Xiang, Bai; Zhang, Lanwei; Li, Minyong; Li, Yuanpei

Abstract

Smart conversion of supramolecular structures in vivo is an attractive strategy in cancer nanomedicine, which is usually achieved via specific peptide sequences. Here we developed a lysosomal targeting small‐molecule conjugate, PBC, which self‐assembles into nanoparticles at physiological pH and smartly converts to nanofibrils in lysosomes of tumor cells. Such a transformation mechanically leads to lysosomal dysfunction, autophagy inhibition, and unusual cytoplasmic vacuolation, thus granting PBC a unique anticancer activity as a monotherapy. Importantly, the photo‐activated PBC elicits significant phototoxicity to lysosomes and shows enormous advantages in overcoming autophagy‐caused treatment resistance frequently occurring in conventional phototherapy. This improved phototherapy achieves a complete cure of oral cancer xenografts upon limited administration. Our work provides a new paradigm for the construction of nonpeptide nanotransformers with biomedical activities.

Subjects

LYSOSOMES; AMINO acid sequence; NANOMEDICINE; ORAL cancer; ANTINEOPLASTIC agents; PHOTOTHERAPY; AUTOPHAGY

Publication

Angewandte Chemie, 2022, Vol 134, Issue 35, p1

ISSN

0044-8249

Publication type

Academic Journal

DOI

10.1002/ange.202204567