Drug-Loaded Nanogel for Efficient Orchestration of Cell Death Pathways by Intramitochondrial Disulfide Polymerization

Abstract

Chemotherapy using a nanoscaled drug delivery system is an effective cancer therapy, but its high drug concentration often causes drug resistance in cancer cells and normal cell damage. Combination therapy involving two or more different cell signaling pathways can be a powerful tool to overcome the limitations of chemotherapy. Herein, this article presents nanogel (NG)-mediated co-delivery of a chemodrug camptothecin (CPT) and mitochondria-targeting monomer (MT monomer) for efficient activation of two modes of the programmed cell death pathway (apoptosis and necroptosis) and synergistic enhancement of cancer therapy. CPT and the monomer are incorporated together into the redox-degradable polymeric NGs for release in response to the intracellular glutathione. The MT monomer is shown to undergo reactive oxygen species (ROS)-triggered disulfide polymerization inside the cancerous mitochondria in cooperation with the chemotherapeutic CPT elevating the intracellular ROS level. The CPT/monomer interconnection in cell death mechanisms for mitochondrial dysfunction and enhanced cell death is evidenced by a series of cell analyses showing ROS generation, mitochondria damage, impacts on (non)cancerous or drug-resistant cells, and cell death modes. The presented work provides beneficial insights for utilizing combination therapy to facilitate a desired cell death mechanism and developing a novel nanosystem for more efficacious cancer treatment. An anticancer drug camptothecin (CPT) and mitochondria-targeting monomer are simultaneously delivered into cancer cells by glutathione-degradable nanogels for cooperative activation of cell death mechanisms. With the assistance of CPT to raise the intracellular level of reactive oxygen species (ROS), the mitochondria-accumulated monomer undergoes ROS-triggered disulfide polymerization with high efficiency, leading to mitochondrial dysfunction and enhanced cell death.image