title: Nanoparticle-mediated dual delivery of an antioxidant and a peptide against the L-Type Ca2+ channel enables simultaneous reduction of cardiac ischemia-reperfusion injury.
abstract: Increased reactive oxygen species (ROS) production and elevated intracellular Ca(2+) following cardiac ischemia-reperfusion injury are key mediators of cell death and the development of cardiac hypertrophy. The L-type Ca(2+) channel is the main route for calcium influx in cardiac myocytes. Activation of the L-type Ca(2+) channel leads to a further increase in mitochondrial ROS production and metabolism. We have previously shown that the application of a peptide derived against the alpha-interacting domain of the L-type Ca(2+) channel (AID) decreases myocardial injury post reperfusion. Herein, we examine the efficacy of simultaneous delivery of the AID peptide in combination with the potent antioxidants curcumin or resveratrol using multifunctional poly(glycidyl methacrylate) (PGMA) nanoparticles. We highlight that drug loading and dissolution are important parameters that have to be taken into account when designing novel combinatorial therapies following cardiac ischemia-reperfusion injury. In the case of resveratrol low loading capacity and fast release rates hinder its applicability as an effective candidate for simultaneous therapy. However, in the case of curcumin, high loading capacity and sustained release rates enable its effective simultaneous delivery in combination with the AID peptide. Simultaneous delivery of the AID peptide with curcumin allowed for effective attenuation of the L-type Ca(2+) channel-activated increases in superoxide (assessed as changes in DHE fluorescence; Empty NP = 53.1 ± 7.6%; NP-C-AID = 7.32 ± 3.57%) and mitochondrial membrane potential (assessed as changes in JC-1 fluorescence; Empty NP = 19.8 ± 2.8%; NP-C-AID=13.05 ± 1.78%). We demonstrate in isolated rat hearts exposed to ischemia followed by reperfusion, that curcumin and the AID peptide in combination effectively reduce muscle damage, decrease oxidative stress and superoxide production in cardiac myocytes.
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia , Crawley, Western Australia 6009, Australia.
authors.forename: Naviin
authors.initials: N
authors.lastname: Hardy
authors.forename: Helena M
authors.initials: HM
authors.lastname: Viola
authors.forename: Victoria P A
authors.initials: VP
authors.lastname: Johnstone
authors.forename: Tristan D
authors.initials: TD
authors.lastname: Clemons
authors.forename: Henrietta
authors.initials: H
authors.lastname: Cserne Szappanos
authors.forename: Ruhani
authors.initials: R
authors.lastname: Singh
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Smith
authors.forename: K Swaminathan
authors.initials: KS
authors.lastname: Iyer
authors.forename: Livia C
authors.initials: LC
authors.lastname: Hool
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000737:chemistry*; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D004347:Drug Interactions; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D011094:Polyethyleneimine / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D020746:Calcium Channels, L-Type; D004337:Drug Carriers; D010446:Peptide Fragments; D011109:Polymethacrylic Acids; D013267:Stilbenes; D013481:Superoxides; C042535:polyglycidyl methacrylate; D011094:Polyethyleneimine; D003474:Curcumin; D000077185:Resveratrol
keywords: L-type Ca2+ channel; antioxidant; curcumin; ischemia-reperfusion injury; nanoparticles; resveratrol