title: Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction.
abstract: Although reperfusion is essential in restoring circulation to ischemic myocardium, it also leads to irreversible events including reperfusion injury, decreased cardiac function and ultimately scar formation. Various cell types are involved in the multi-phase repair process including inflammatory cells, vascular cells and cardiac fibroblasts. Therapies targeting these cell types in the infarct border zone can improve cardiac function but are limited by systemic side effects. The aim of this work was to develop liposomes with surface modifications to include peptides with affinity for cell types present in the post-infarct myocardium. To identify peptides specific for the infarct/border zone, we used in vivo phage display methods and an optical imaging approach: fluorescence molecular tomography (FMT). We identified peptides specific for cardiomyocytes, endothelial cells, myofibroblasts, and c-Kit + cells present in the border zone of the remodeling infarct. These peptides were then conjugated to liposomes and in vivo specificity and pharmacokinetics were determined. As a proof of concept, cardiomyocyte specific (I-1) liposomes were used to deliver a PARP-1 (poly [ADP-ribose] polymerase 1) inhibitor: AZ7379. Using a targeted liposomal approach, we were able to increase AZ7379 availability in the infarct/border zone at 24h post-injection as compared with free AZ7379. We observed ~3-fold higher efficiency of PARP-1 inhibition when all cell types were assessed using I-1 liposomes as compared with negative control peptide liposomes (NCP). When analyzed further, I-1 liposomes had 9-fold and 1.5-fold higher efficiencies in cardiomyocytes and macrophages, respectively, as compared with NCP liposomes. In conclusion, we have developed a modular drug delivery system that can be targeted to cell types of therapeutic interest in the infarct border zone.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Siva Sai Krishna
authors.initials: SSK
authors.lastname: Dasa
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA; Laboratory of Drug and Gene Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gutknecht
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.
authors.forename: Lindsey T
authors.initials: LT
authors.lastname: Brinton
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Yikui
authors.initials: Y
authors.lastname: Tian
authors.affiliation: IMed CVMD Bioscience, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Michaelsson
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Lindfors
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA; Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: French
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. Electronic address: kak3x@virginia.edu.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001682:Biological Availability; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D061505:Cell Surface Display Techniques; D004195:Disease Models, Animal; D004339:Drug Compounding; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019151:Peptide Library; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility
chemical_list: D002317:Cardiovascular Agents; D008055:Lipids; D008081:Liposomes; D019151:Peptide Library; D010455:Peptides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: Drug delivery; Myocardial infarction; Neoangiogenesis; Phage display; Pharmacodynamics