Targeting of macromolecular carriers and liposomes by antibodies to myosin heavy chain

Klibanov, Alexander L.; Khaw, Ban An; Nossiff, Naseem; O’Donnell, Sean; Huang, Leaf; Slinkin, M. A.; Torchilin, Vladimir P.

doi:10.1152/ajplung.1991.261.4.l60

Cited by 3 publications

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“…This hypothesis led to the development of a cardiac myosin-specific antibody, 2G4, which has been used to facilitate the uptake of ATP by several different versions of immunoliposomes containing primarily phosphatidyl choline, cholesterol, and 1,2-dioleoyl-sn-glycero-3-phophoethanolamine (DOPE) and PEG [74–77]. The use of these immunoliposomes was demonstrated to efficiently transfect H9C2 cells in vitro, but in vivo experimentation never followed [78].…”

Section: Non-viral Targeting Vectors Of Myocardiummentioning

confidence: 99%

Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction

Yockman

Kastenmeier

Erickson

et al. 2008

Journal of Controlled Release

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The number one cause of mortality in the US is cardiovascular related disease. Future predictions do not see a reduction in this rate especially with the continued rise in obesity [1,2]. Even so, potential molecular therapeutic targets for cardiac gene delivery are in no short supply thanks to continuing advances in molecular cardiology. However, efficient and safe delivery remains a bottleneck in clinical gene therapy [3] Keywords myocardium; angiogenesis; non-viral gene delivery; ischemia Viral vectors are looked upon favorably for their high transduction efficiency, although their ability to elicit toxic immune responses remains [4]. However, this high transduction does not necessarily translate into improved efficacy [5]. Naked DNA remains the preferred method of DNA delivery to cardiac myocardium and has been explored extensively in clinical trials. The results from these trials have demonstrated efficacy in regards to secondary end-points of reduced symptomology and perfusion, but have failed to establish significant angiogenesis or an increase in myocardial function [6]. This may be due in part to reduced transfection efficiency but can also be attributed to use of suboptimal candidate genes.Correspondence should be addressed to: David A. Bull, M.D., Division of Cardiothoracic Surgery, Room 3C127, 30 North 1900 East, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, Phone 801-581-5311, FAX 801-585-3936, david.bull@hsc.utah.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. However, little development has been seen in the use of new gene agents for treatment of myocardial ischemia and infarction. Current treatment consists of using mitogenic factors, described decades earlier, alone or in combination to spur angiogenesis or modulating intracellular Ca2+ homeostasis through SERCA2a but have to date, failed to demonstrate clinical efficacy. Recent data suggests that axonal guidance cues also act on vasculature neogenesis and provide a new means of investigation for treatment. NIH Public Access Clinical Gene Therapy for Therapeutic Myocardial AngiogenesisIschemic heart disease is the leading cause of death in the United States today. Currently, the mainstay of therapy for ischemic heart disease (IHD) is revascularization. Nearly 2,000,000 cardiac catheterizations and 553,000 coronary artery bypass grafting procedures are performed annually [9]. Technological developments in these areas have led to an improved survival and quality of life for patients with IHD. However, increasing evidence suggests that revascularization alone is insuffici...

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Section: Non-viral Targeting Vectors Of Myocardiummentioning

confidence: 99%

Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction

Yockman

Kastenmeier

Erickson

et al. 2008

Journal of Controlled Release

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Emanuel¹,

Kedar

Bolotin

et al. 1996

Pharmaceutical Research

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Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

et al. 2018

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Rationale: Cardiac stem cell-derived exosomes have been demonstrated to promote cardiac regeneration following myocardial infarction in preclinical studies. Recent studies have used intramyocardial injection in order to concentrate exosomes in the infarct. Though effective in a research setting, this method is not clinically appealing due to its invasive nature. We propose the use of a targeting peptide, cardiac homing peptide (CHP), to target intravenously-infused exosomes to the infarcted heart.Methods: Exosomes were conjugated with CHP through a DOPE-NHS linker. Ex vivo targeting was analyzed by incubating organ sections with the CHP exosomes and analyzing with fluorescence microscopy. In vitro assays were performed on neonatal rat cardiomyocytes and H9C2 cells. For the animal study, we utilized an ischemia/reperfusion rat model. Animals were treated with either saline, scramble peptide exosomes, or CHP exosomes 24 h after surgery. Echocardiography was performed 4 h after surgery and 21 d after surgery. At 21 d, animals were sacrificed, and organs were collected for analysis.Results: By conjugating the exosomes with CHP, we demonstrate increased retention of the exosomes within heart sections ex vivo and in vitro with neonatal rat cardiomyocytes. In vitro studies showed improved viability, reduced apoptosis and increased exosome uptake when using CHP-XOs. Using an animal model of ischemia/reperfusion injury, we measured the heart function, infarct size, cellular proliferation, and angiogenesis, with improved outcomes with the CHP exosomes.Conclusions: Our results demonstrate a novel method for increasing delivery of for treatment of myocardial infarction. By targeting exosomes to the infarcted heart, there was a significant improvement in outcomes with reduced fibrosis and scar size, and increased cellular proliferation and angiogenesis.

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Targeting of macromolecular carriers and liposomes by antibodies to myosin heavy chain

Cited by 3 publications

References 0 publications

Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction

Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction

Untitled

Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

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