H2S‐Responsive Small‐Molecule Nanocarriers for Drug Delivery to Colorectal Tumors

Abstract Hydrogen sulfide (H 2 S), a gaseous signaling molecule, is excessively produced in disease lesions like lung tumors and colorectal tumors. H 2 S is used as a trigger for stimuli‐responsive drug delivery in cancer therapies, which enables controlled release of chemotherapeutics and improves their biocompatibility and efficacy. Herein, a H 2 S‐responsive small‐molecule nanocarrier is developed based on the self‐assembly of a trigonal molecule, tris (azido benzyl)‐tri(2‐aminoethyl) amine (ATAEA). ATAEA with three H 2 S‐responsive azido benzyl groups can self‐assemble into nanocarriers (ATNPs) and encapsulate hydrophobic doxorubicin (DOX) to form drug‐loaded nanoparticles (DOX/ATNPs). H 2 S induces the reduction of azido benzyl group and 1,6‐elimination, which results in the dissociation of the ATAEA molecules and the nanoparticles. In HCT116 colon cancer cells, efficient H 2 S‐responsive DOX release from DOX/ATNPs is observed. In vivo administration of DOX/ATNPs in colon tumor‐bearing mice leads to higher drug accumulation in tumors and evident tumor growth inhibition, in comparison with non‐responsive nanoparticles. This work provides a new strategy to develop H 2 S‐responsive drug delivery systems for precise drug delivery to H 2 S‐enriched disease lesions.