(584ac) Dual Acid-Responsive Anticancer Polymeric Micelles As New Anticancer Therapeutics

Cinnamaldehyde is a major component in cinnamon, which is an important dietary factor and food additive and is known induce apoptotic cell death through ROS (reactive oxygen species) generation. Despite its potent anticancer activities, the use of cinnamaldehyde in clinical applications is limited by its poor stability and lack of specificity toward diseased tissues. In order to exploit cinnamaldehyde as anticancer drugs, we developed dual acid-sensitive polymeric prodrug of cinnamaldehyde, poly(cinnamaldehyde-co-β-amino ester)-co-poly(ethylene glycol)(PCAE), which incorporates therapeutic cinnamaldehyde covalently in its backbone through acid-cleavable acetal linkages and release it to induce ROS-mediated apoptotic cell death. PCAE copolymers have average molecular weight ~10,000Da and self-assemble to form monodispersed micelles with a mean hydrodynamic diameter of ~90 nm.  PCAE micelles have dual acid-sensitive behaviors, micelle dissociation and cinnamaldehyde release due to the presence of amine groups and acid-labile acetal linkages.  PCAE micelles induced the ROS-mediated apoptotic cell death in SW620 cells, evidenced by confocal laser scanning micrographs and flow cytomety. We also investigated the ability of PCAE micelles to deliver anticancer drugs, camptothecin (CPT) as a model drug, which triggers ROS generation to induce apoptotic cell death.  CPT was loaded at a concentration of 10 wt% of micelles with ~90% encapsulation efficiency. CPT-loaded PCAE micelles induced significantly more ROS generation and apoptotic cell death than free CPT and PCAE micelles, suggesting that PCAE micelles have potential as drug carriers and are able to exert synergistic effects with CPT on ROS-mediated apoptotic cell death generation. In a tumor-bearing mice, PCAE micelles also reduced the tumor growth and showed synergistic anticancer activities with a payload of CPT. We anticipate that dual pH-responsive PCAE micelles are able to serve as anticancer drugs as well as drug carriers and have enormous potential as novel anticancer therapeutics.