Examining Efficacy of “TAT-less” Delivery of a Peptide against the L‑Type Calcium Channel in Cardiac Ischemia–Reperfusion Injury

• Published in: ACS nano Vol. 7; no. 3; pp. 2212 - 2220
• Main Authors: Clemons, Tristan D, Viola, Helena M, House, Michael J, Iyer, K. Swaminathan, Hool, Livia C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.03.2013
• Subjects: Amino Acid Sequence; Animals; Biological Transport, Active; Calcium; Calcium Channel Blockers - administration & dosage; Calcium Channels, L-Type - chemistry; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Channels; Drug Delivery Systems; Effectiveness; Guinea Pigs; Injuries; Kinases; Magnetite Nanoparticles - administration & dosage; Magnetite Nanoparticles - chemistry; Magnetite Nanoparticles - ultrastructure; Models, Molecular; Molecular Sequence Data; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - metabolism; Myocytes, Cardiac - metabolism; Nanoparticles; Nanostructure; Nanotechnology; Peptide Fragments - administration & dosage; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptides; Protein Structure, Tertiary; nanoparticle; ischemia−reperfusion; peptide delivery
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/nn305211f

Increased calcium influx through the L-type Ca2+ channel or overexpression of the alpha subunit of the channel induces cardiac hypertrophy. Cardiac hypertrophy results from increased oxidative stress and alterations in cell calcium levels following ischemia–reperfusion injury and is an independent risk factor for increased morbidity and mortality. We find that decreasing the movement of the auxiliary beta subunit with a peptide derived against the alpha-interacting domain (AID) of the channel attenuates ischemia–reperfusion injury. We compared the efficacy of delivering the AID peptide using a trans-activator of transcription (TAT) sequence with that of the peptide complexed to multifunctional polymeric nanoparticles. The AID-tethered nanoparticles perfused through the myocardium more diffusely and associated with cardiac myocytes more rapidly than the TAT-labeled peptide but had similar effects on intracellular calcium levels. The AID-complexed nanoparticles resulted in a similar reduction in release of creatine kinase and lactate dehydrogenase after ischemia–reperfusion to the TAT-labeled peptide. Since nanoparticle delivery also holds the potential for dual drug delivery, we conclude that AID-complexed nanoparticles may provide an effective platform for peptide delivery in cardiac ischemia–reperfusion injuries.