Notch Pathway Deactivation\nSensitizes Breast Cancer\nStem Cells toward Chemotherapy Using NIR Light-Responsive Nanoparticles

Chemotherapy remains a major therapeutic approach to\ncancer treatment.\nHowever, its effectiveness can be compromised by the heterogeneity\nof a solid tumor, in which different cancer cell populations display\nvaried responses to chemotherapy. Such an intratumor heterogeneous\nstructure is maintained by the cancer stem-like cells (CSCs) with\ninherent capacities for self-renewal and differentiation, giving rise\nto diverse cell populations. To address this, we proposed a combinational\nstrategy in which tumor lesion-targeted Notch signaling regulation\nwas achieved to disrupt CSC-mediated cancer heterogeneity, thereby\nsensitizing solid tumors toward paclitaxel (PTX). Specifically, gamma-secretase\ninhibitor LY-411,575 was co-delivered with PTX using a near-infrared\n(NIR) light-controlled drug delivery system to realize targeted ablation\nof both differentiated cancer cells and undifferentiated CSCs. By\nenabling precise regulation of the Notch pathway at the tumor site\nthrough NIR light, we observed significantly elevated efficacy of\nchemotherapy and notable prevention of postsurgical tumor relapse\nwhile minimizing systemic side effects. The devised strategy shows\npromise in addressing the nonspecific inhibition of stemness across\nvarious organs, a challenge that hampers the clinical translation\nof gamma-secretase inhibitors in cancer therapy.