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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.

SUBMITTER: Dasa SSK

PROVIDER: S-EPMC6113056 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction.

Dasa Siva Sai Krishna SSK Suzuki Ryo R Gutknecht Michael M Brinton Lindsey T LT Tian Yikui Y Michaelsson Erik E Lindfors Lennart L Klibanov Alexander L AL French Brent A BA Kelly Kimberly A KA

Journal of controlled release : official journal of the Controlled Release Society 20150627 Pt A

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 ...[more]

PMID: 26122651

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Project description:PurposeNitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.MethodsTo analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining.ResultsThree weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5) and end-diastolic volumes (82.7±5.6 μl; *p<0.05; n = 5) were significantly increased in BC-/EC+, along with decreased LV developed pressure (67.5±1.8 mm Hg; n = 18; ***p≤0.001) and increased scar size/left ventricle (19.5±1.5%; n = 13; **p≤0.01) compared to BC+/EC+ (ESV: 35.6±2.2 μl; EDV: 69.1±2.6 μl n = 8; LVDP: 83.2±3.2 mm Hg; n = 24; scar size/LV13.8±0.7%; n = 16). Myocardial scar of BC-/EC+ was characterized by increased total collagen content (20.2±0.8%; n = 13; ***p≤0.001) compared to BC+/EC+ (15.9±0.5; n = 16), and increased collagen type I and III subtypes.ConclusionCirculating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.

Project description:BackgroundThe success of coronary reperfusion therapy in ST-segment-elevation myocardial infarction (MI) is commonly limited by failure to restore microvascular perfusion.Methods and resultsWe performed a prospective cohort study in patients with reperfused ST-segment-elevation MI who underwent cardiac magnetic resonance 2 days (n=286) and 6 months (n=228) post MI. A serial imaging time-course study was also performed (n=30 participants; 4 cardiac magnetic resonance scans): 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. Myocardial hemorrhage was taken to represent a hypointense infarct core with a T2* value of <20 ms. Microvascular obstruction was assessed with late gadolinium enhancement. Adverse remodeling was defined as an increase in left ventricular end-diastolic volume ≥20% at 6 months. Cardiovascular death or heart failure events post discharge were assessed during follow-up. Two hundred forty-five patients had evaluable T2* data (mean±age, 58 [11] years; 76% men). Myocardial hemorrhage 2 days post MI was associated with clinical characteristics indicative of MI severity and inflammation. Myocardial hemorrhage was a multivariable associate of adverse remodeling (odds ratio [95% confidence interval]: 2.64 [1.07-6.49]; P=0.035). Ten (4%) patients had a cardiovascular cause of death or experienced a heart failure event post discharge, and myocardial hemorrhage, but not microvascular obstruction, was associated with this composite adverse outcome (hazard ratio, 5.89; 95% confidence interval, 1.25-27.74; P=0.025), including after adjustment for baseline left ventricular end-diastolic volume. In the serial imaging time-course study, myocardial hemorrhage occurred in 7 (23%), 13 (43%), 11 (33%), and 4 (13%) patients 4 to 12 hours, 2 days, 10 days, and 7 months post reperfusion. The amount of hemorrhage (median [interquartile range], 7.0 [4.9-7.5]; % left ventricular mass) peaked on day 2 (P<0.001), whereas microvascular obstruction decreased with time post reperfusion.ConclusionsMyocardial hemorrhage and microvascular obstruction follow distinct time courses post ST-segment-elevation MI. Myocardial hemorrhage was more closely associated with adverse outcomes than microvascular obstruction.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850.

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Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction.

Publications

Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction.

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