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

Hydrogen sulfide releasing agents (or H 2 S donors) have been recognized gasotransmitters with potent cytoprotective and anticancer properties. However, the clinical application of H 2 S donors has been hampered by their fast H 2 S-release, instability, and lack of tumor targeting, despite the unclear molecular mechanism of H 2 S action. Here we rationally designed an amphiphilic pentapeptide (RGDFF) to coassemble with the de novo designed thiol-activated H 2 S 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 H 2 S release while dramatically improving their biocompatible interface, circulation time, slow release of H 2 S, 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 H 2 S-producing enzymes, and lead to mitochondrial dysfunction by increasing intracellular ROS production in H1299 cells. The mouse tumorigenesis experiments further confirmed the in vivo 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.