Engineered polymeric micelles for combinational oxidation anticancer therapy through concurrent ho-1 inhibition and ros generation

Statement of Purpose: Cancer cells are under oxidative stress due to an elevated level of ROS (reactive oxygen species) and therefore undertake redox adaptation to drive proliferation in tumor environments and even survive during anticancer treatment by upregulating endogenous antioxidants. Heme oxygenase-1 (HO-1) is one of antioxidant defense systems, playing vital roles in tumor growth by providing antioxidant bilirubin to protect cancer cells under stress conditions. It can be therefore reasoned that the combination of ROS generation and HO-1 inhibition synergistically elevates oxidative stress and provides a new powerful means to induce selective toxicity toward cancer cells. To establish targeted anticancer therapy based on amplified oxidative stress, we developed molecularly engineered polymer, termed CZP, which incorporates ROS generating CA (cinnamaldehyde) and HO-1 inhibiting ZnPP (zinc protoporphyrin) in its backbone. In this work, we present the therapeutic potential of CZP evaluated from the extensive studies of cell culture models and xenograft mouse models.