Cinnamaldehyde, a major active compound of cinnamon, is known to induce apoptotic cell death in numerous human cancer cells. Here, 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 copolymers, are reported. PCAE is designed to incorporate cinnamaldehyde via acid-cleavable acetal linkages in its pH-sensitive hydrophobic backbone and self assemble to form stable micelles which can encapsulate camptothecin (CPT). PCAE self assembles to form micelles which release CPT and cinnamaldehyde in pHdependent manners. PCAE micelles induce apoptotic cell death through the generation of intracellular reactive oxygen species (ROS) and exert synergistic anticancer effects with a payload of CPT in vitro and in vivo model of SW620 human colon tumor-bearing mice. It is anticipated that dual acid-sensitive micelle-forming PCAE with intrinsic anticancer activities has enormous potential as novel anticancer therapeutics.
Background and purposeCinnamaldehyde, a major component of cinnamon, induces the generation of reactive oxygen species and exerts vasodilator and anticancer effects, but its short half-life limits its clinical use. The present experiments were designed to compare the acute relaxing properties of cinnamaldehyde with those of self-assembling polymer micelles either loaded with cinnamaldehyde or consisting of a polymeric prodrug [poly(cinnamaldehyde)] that incorporates the compound in its backbone.MethodsRings of porcine coronary arteries were contracted with the thromboxane A2 receptor agonist U46619 or 40 mM KCl, and changes in isometric tension were recorded.ResultsCinnamaldehyde induced concentration-dependent but endothelium-independent, nitric oxide synthase (NOS)-independent, cyclooxygenase-independent, soluble guanylyl cyclase (sGC)-independent, calcium-activated potassium-independent, and TRPA1 channel-independent relaxations. Cinnamaldehyde also inhibited the contractions induced by 40 mM KCl Ca2+ reintroduction in 40 mM KCl Ca2+-free solution or by the Ca2+ channel opener Bay K8644. Cinnamaldehyde-loaded control micelles induced complete, partly endothelium-dependent relaxations sensitive to catalase and inhibitors of NOS or sGC, but not cyclooxygenase or TRPA1, channels. Cinnamaldehyde-loaded micelles also inhibited contractions induced by 40 mM KCl Ca2+ reintroduction or Bay K8644. Poly(cinnamaldehyde) micelles induced only partial, endothelium-dependent relaxations that were reduced by inhibitors of NOS or sGC and by catalase and the antioxidant tiron, but not by indomethacin or TRPA1 channel blockers.ConclusionThe present findings demonstrate that cinnamaldehyde-loaded and poly(cinnamaldehyde) micelles possess vasodilator properties, but that the mechanism underlying the relaxation that they cause differs from that of cinnamaldehyde, and thus could be used both to relieve coronary vasospasm and for therapeutic drug delivery.
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