Co-assembled Nanocarriers of <i>De Novo</i> Thiol-Activated Hydrogen Sulfide Donors with an RGDFF Pentapeptide for Targeted Therapy of Non-Small-Cell Lung Cancer

Abstract

Hydrogen sulfide releasing agents (or H₂S donors) have been recognized gasotransmitters with potent cytoprotective and anticancer properties. However, the clinical application of H₂S donors has been hampered by their fast H₂S-release, instability, and lack of tumor targeting, despite the unclear molecular mechanism of H₂S action. Here we rationally designed an amphiphilic pentapeptide (RGDFF) to coassemble with the <i>de novo</i> designed thiol-activated H₂S donors (CL2/3) into nanocarriers for targeted therapy of non-small-cell lung cancer, which has been proved as a one-stone-three-birds strategy. The coassembly approach simply solved the solubility issue of CL2/3 by the introduction of electron-donating groups (phenyl rings) to slow down the H₂S release while dramatically improving their biocompatible interface, circulation time, slow release of H₂S, and tumor targeting. Experimental results confirmed that as-prepared coassembled nanocarriers can significantly induce the intrinsic apoptotic, effectively arrest cell cycle at the G2/M phase, inhibit H₂S-producing enzymes, and lead to mitochondrial dysfunction by increasing intracellular ROS production in H1299 cells. The mouse tumorigenesis experiments further confirmed the <i>in vivo</i> anticancer effects of the coassembled nanocarriers, and such treatment made tumors more sensitive to radiotherapy then improved the prognosis of tumor-bearing mice, which holds great promise for developing a new combined approach for NSCLC.