Reactive oxygen species (ROS) are a collective term of highly reactive chemical species and radicals, including hydrogen peroxide, superoxide anion and hydroxyl radical. Compared to normal cells, cancer cells are under oxidative stress associated with the elevated level of ROS and are more vulnerable to oxidative stress induced by ROS generating agents. In addition, ROS produced by host phagocytes exert antibacterial action against a variety of pathogens and ROS-induced oxidative stress is the governing mechanism for the antibacterial activity of major bactericidal antibiotics. Thus, manipulation of the ROS level provides a logical approach to kill cancer cells and bacteria specifically, without toxicity to normal cells. Cinnamaldehyde, a major active compound of cinnamon, exerts antibacterial and anticancer activity by generating ROS. However, its clinical uses are limited by poor bioavailability and low therapeutic efficacy. In order to overcome these limitations, we developed dual acid-responsive polymeric micelle-forming cinnamaldehyde prodrugs, poly[(3-phenylprop-2-ene-1,1-diyl)bis(oxy)bis(ethane-2,1-diyl)diacrylate]-co-4,4’(trimethylene dipiperidine)-co-poly (ethylene glycol), termed PCAE. PCAE is designed to incorporate cinnamaldehyde via acid-cleavable acetal linkages in its pH-sensitive backbone and self-assemble to form stable micelles which can encapsulate common therapeutic agents. PCAE self-assembles to form micelles which release drug payloads and cinnamaldehyde in pH-dependent manners. PCAE micelles induce apoptotic cell death through ROS generation and exert synergistic therapeutic effects with a payload in a mouse model of tumor xenografts. Moreover, PCAE micelles encapsulating ferrocene could perform Fenton reaction to generate hydroxyl radicals which kill bacteria in a mouse model of bacterial infection. We anticipate that ROS-generating PACE has great potential for anticancer and antibacterial therapy.

Acid-triggered oxidative stress amplifying polymeric micelles: Applications in anticancer and antibacterial therapy

251st National Meeting (2016)

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