title: Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction.
abstract: Recent developments in nanotechnology have created considerable potential toward diagnosis and cancer therapy. In contrast, the use of nanotechnology in tissue repair or regeneration remains largely unexplored. We hypothesized that intramyocardial injection of insulin-like growth factor (IGF)-1-complexed poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (PLGA-IGF-1 NPs) increases IGF-1 retention, induces Akt phosphorylation, and provides early cardioprotection after acute myocardial infarction (MI). We synthesized 3 different sizes of PLGA particles (60 nm, 200 nm, and 1 μm) which were complexed with IGF-1 using electrostatic force to preserve the biological function of IGF-1. Afterward, we injected PLGA-IGF-1 NPs in the heart after MI directly. Compared with the other two larger particles, the 60 nm-sized PLGA-IGF-1 NPs carried more IGF-1 and induced more Akt phosphorylation in cultured cardiomyocytes. PLGA-IGF-1 NPs also prolonged Akt activation in cardiomyocytes up to 24h and prevented cardiomyocyte apoptosis induced by doxorubicin in a dose-dependent manner. In vivo, PLGA-IGF-1 NP treatment significantly retained more IGF-1 in the myocardium than the IGF-1 alone treatment at 2, 6, 8, and 24 h. Akt phosphorylation was detected in cardiomyocytes 24h post-MI only in hearts receiving PLGA-IGF-1 NP treatment, but not in hearts receiving injection of PBS, IGF-1 or PLGA NPs. Importantly, a single intramyocardial injection of PLGA-IGF-1 NPs was sufficient to prevent cardiomyocyte apoptosis (P<0.001), reduce infarct size (P<0.05), and improve left ventricle ejection fraction (P<0.01) 21 days after experimental MI in mice. Our results not only demonstrate the potential of nanoparticle-based technology as a new approach to treating MI, but also have significant implications for translation of this technology into clinical therapy for ischemic cardiovascular diseases.
authors.affiliation: Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ming-Yao
authors.initials: MY
authors.lastname: Chang
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Yang
authors.forename: Chih-Han
authors.initials: CH
authors.lastname: Chang
authors.forename: Alan C L
authors.initials: AC
authors.lastname: Tang
authors.forename: Wei-Yin
authors.initials: WY
authors.lastname: Liao
authors.forename: Fong-Yu
authors.initials: FY
authors.lastname: Cheng
authors.forename: Chen-Sheng
authors.initials: CS
authors.lastname: Yeh
authors.forename: James J
authors.initials: JJ
authors.lastname: Lai
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Stayton
authors.forename: Patrick C H
authors.initials: PC
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage* / Q000737:chemistry; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D007334:Insulin-Like Growth Factor I; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt
keywords: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; Akt; Apoptosis; Cardiomyocyte; EDC; FS; Heart failure; IGF-1; IVSd; Insulin-like growth factor-1; LVEDd; LVEF; LVESd; MI; NPs; PLGA; QDs; fractional shortening; insulin-like growth factor-1; inter ventricular septum dimension; left ventricle ejection fraction; left ventricular end-diastolic dimension; left ventricular end-systolic dimension; myocardial infarction; nanoparticles; poly(d,l-lactide-co-glycolide); quantum dots