Molecular biology reveals that oxygen stress caused by highly reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress associated with misfolded proteins are common phenomena in cancer cells. It leads to resistance of the cancer cells to chemotherapy or photodynamic therapy.Disruption of microenvironmental homeostasis of stress can increase tumor sensitivity to traditional chemotherapeutic drugs, and improve the efficacy of photodynamic therapy (PDT) as well.
The group leading by Professor Qun-Dong Shen at School of Chemistry and Chemical Engineering, Nanjing University, has designed a multimodal anticancer nanoplatform that associates the regulation of the intracellular stress with photodynamic therapy (Small, DOI: 10.1002/smll.201900212). The nanoplatform is composed of ROS-sensitive polymer with chemically linked 2-deoxy-glucose (2-DG) for activation of ER stress, chemotherapy drug doxorubicin (DOX), and photosensitizer for photodynamic therapy. The photosensitizer also emits near-infrared fluorescence, and thus is utilized to reveal accumulation of the nanoplatforminto the tumor site. The reactive oxygen produced by photodynamic therapy results in the release of 2-DG molecules from the nanoplatform. It induces ER stress in the cells, which in turn improves the effect of oxidative stress by PDT on killing cancer cells, as well as the cytotoxicity of chemotherapy drug. As a whole, the nanoplatform can effectively promote the apoptosis of tumor.
Figure 1. Regulation of the microenvironment by the multimodal nanoplatform within the cancer cells.
Their study confirms that, after internalization into the cancer cells, the nanoplatform can readily release its cargoes. It significantly up-regulates apoptosis pathways under ER stress, increases the ROS concentration by photodynamic effect, and promotes outflow of cytochrome C in mitochondria, and finally induces the necrotic or apoptosis of the cancer cells.Inhibition of tumor growth is also demonstrated. It highlights the importance of multiple intracellular stresses, which can be brought out by elaborate design of the functional nanomaterials, in cell biology, immune response, as well as medical treatments of cancer, Alzheimer’s disease, etc.
In recent years, Shen's group has focused on the functional polymers for integrated systems of medical diagnosis and treatment. The first author is Mei Dong, a doctoral candidate. The work is supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, and Program for Changjiang Scholars and Innovative Research Team in University.