Small Molecule-Mediated Chemo-Photodynamic Therapy Induces Autophagy and Apoptosis in Cancer Cells

Cancer is the second leading cause of death globally, which can be treated through invasive chemotherapeutic strategies, leading to severe toxic side effects, injury, and trauma to the patients. Recently, phototherapy gained lots of attention as an alternative, non-invasive cancer therapy. However, developing novel small molecules as chemophototherapeutic agents remained a major challenge. To address this, herein, we have designed and synthesized a small molecule library consisting of aromatic moieties as π-donor, 3-methoxy-pyrrole as π-electron-rich pharmacophore, and cyanine or N-methyl-quinolinium ion as π-acceptor in a concise strategy. Upon screening in colon (HCT-116), cervical (HeLa), and lung (A549) cancer cells, one small molecule (6a) was identified to induce remarkable HCT-116 cell killing under 740 nm LED irradiation by generating a diverse array of reactive oxygen species (ROS) and showing negligible toxicity toward non-cancerous, kidney fibroblast-like Cos-7 cells. Interestingly, compound 6a self-assembled into spherical nanoparticles that homed into the lysosomal compartment of HCT-116 cells efficiently within 3 h, impaired the lysosomal membrane, followed by induction of autophagy and generation of ROS to trigger late apoptosis and necrosis with increased penetration efficiency in 3D-HeLa spheroids under light irradiation. Compound 6a can be a tool for the development of a novel chemo-photodynamic probe for cancer therapy.