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Fibrinolytic PLGA nanoparticles for slow clot lysis within abdominal aortic aneurysms attenuate proteolytic loss of vascular elastic matrix.

ABSTRACT: Abdominal aortic aneurysms (AAAs) involve chronic overexpression of proteases in the aortic wall that result in disruption of elastic fibers and consequent loss of vessel elasticity. Nearly 75% of AAAs contain flow-obstructing, fibrin-rich intraluminal thrombi (ILT), which act as a) a bioinert shield, protecting the underlying AAA wall from high hemodynamic stresses, and b) a reservoir of inflammatory cells and proteases that cause matrix breakdown. For these reasons, restoring flow through the aorta lumen and facilitating transmural diffusion of therapeutics from circulation to the AAA wall must be achieved by slow thrombolysis of the ILT to render it porous without rapid breakdown. Intravenously dosed tissue plasminogen activator (tPA) has been shown to rapidly lyse ILTs in acute stroke and myocardial infarctions. For future use in opening up AAA segments, in this study, we investigated the ability of tPA released from poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) to slowly lyse fibrin clots without inducing proteolytic injury and matrix synthesis-inhibitory effects on cultured rat aneurysmal smooth muscle cells (EaRASMCs). Fibrin clot lysis time was greatly extended over that in presence of exogenous tPA. Surface functionalization of NPs with a cationic amphiphile allowed them to bind to anionic fibrin clot, release tPA at a slower rate and to lyse the clot as a front proceeding outwards in unlike the more rapid and homogenous lysis that occurred due to anionic PLGA NPs. Elastic matrix content was decreased in EaRASMC cultures exposed to byproducts of clot lysis with exogenous tPA, but not tPA-NPs, and was likely due to increased proteolytic activity (MMPs, plasmin) in EaRASMC cultures exposed to exogenous tPA-lysed clots. Our results suggest that gradual ILT lysis via slow release of tPA from NPs will be likely beneficial over exogenous tPA delivery in preserving elastic matrix content and attenuating matrilysis in the adjoining AAA wall, in vivo, while rendering the ILT porous to facilitate transmural delivery of endoluminally delivered AAA therapeutics.

SUBMITTER: Sivaraman B

PROVIDER: S-EPMC5784758 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Fibrinolytic PLGA nanoparticles for slow clot lysis within abdominal aortic aneurysms attenuate proteolytic loss of vascular elastic matrix.

Sivaraman Balakrishnan B Sylvester Andrew A Ramamurthi Anand A

Materials science & engineering. C, Materials for biological applications 20150916

Abdominal aortic aneurysms (AAAs) involve chronic overexpression of proteases in the aortic wall that result in disruption of elastic fibers and consequent loss of vessel elasticity. Nearly 75% of AAAs contain flow-obstructing, fibrin-rich intraluminal thrombi (ILT), which act as a) a bioinert shield, protecting the underlying AAA wall from high hemodynamic stresses, and b) a reservoir of inflammatory cells and proteases that cause matrix breakdown. For these reasons, restoring flow through the ...[more]

PMID: 26652359

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Project description:BACKGROUND:The natural history of abdominal aortic aneurysms (AAAs) suggests that some remain slow in growth rate whereas many develop a more accelerated growth rate and reach a threshold for intervention. We hypothesized that different mechanisms are responsible for AAAs that remain slow growing and never become actionable vs the aggressive AAAs that require intervention and may be reflected by distinct associations with genetic polymorphisms. METHODS:AAA growth rate was determined from serial imaging data in 168 control and 141 AAA patients with ultrasound or computed tomography imaging studies covering ?5 years. Genetic polymorphisms all previously reported as showing a significant correlation with AAA with functional effects on the expression or function were determined by analysis of the genomic DNA, including angiotensin 1 receptor (rs5186), interleukin-10 (IL-10; rs1800896), methyl-tetrahydrofolate reductase (rs1801133), low-density lipoprotein receptor-related protein 1 (LRP1; rs1466535), angiotensin-converting enzyme (rs1799752), and several matrix metalloproteinase 9 (MMP-9) single nucleotide polymorphisms. RESULTS:Of the AAA patients, 81 were classified as slow AAA growth rate (<3.25 mm/y) vs 60 with aggressive AAA growth rate (>3.25 mm/y, those presenting with a rupture, or those with maximal aortic diameter >5.5 cm [male] or >5.0 cm [female]). Discriminating confounds between the groups were identified by logistic regression. Analyses identified MMP-9 p-2502 single nucleotide polymorphism (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.31-0.94; P = .029) as a significant confound discriminating between control vs slow-growth AAA, MMP-9 D165N (OR, 0.49; 95% CI, 0.26-0.95; P = .035) and LRP1 (OR, 4.99; 95% CI, 1.13-22.1; P = .034) between control vs aggressive-growth AAAs, and methyltetrahydrofolate reductase (OR, 2.99; 95% CI, 1.01-8.86; P = .048), MMP-9 p-2502 (OR, 2.19; 95% CI, 1.05-4.58; P = .037), and LRP1 (OR, 4.96; 95% CI, 1.03-23.9; P = .046) as the statistically significant confounds distinguishing slow-growth AAAs vs aggressive-growth AAAs. CONCLUSIONS:Logistic regression identified different genetic confounds for the slow-growth and aggressive-growth AAAs, indicating a potential for different genetic influences on AAAs of distinct aggressiveness. Future logistic regression studies investigating for potential genetic or clinical confounds for this disease should take into account the growth rate and size of the AAA to better identify confounds likely to be associated with aggressive AAAs likely to require intervention.

Project description:ImportanceCurrently there is no drug therapy for abdominal aortic aneurysm (AAA).ObjectiveTo test the efficacy of the angiotensin receptor blocker telmisartan in slowing AAA growth in the Telmisartan in the Management of Abdominal Aortic Aneurysm (TEDY) trial.Design, setting, and participantsA randomized, double-blind, placebo-controlled trial recruited participants between September 6, 2011, and October 5, 2016, to evaluate the efficacy of telmisartan treatment in patients with AAA. Participants with 35- to 49-mm AAAs recruited from Australia, the Netherlands, and the US were randomized 1:1 to receive telmisartan, 40 mg, or identical placebo. Analyses were conducted according to intention-to-treat principles. Final follow-up was conducted on October 11, 2018, and data analysis was performed between June and November 2019.InterventionTelmisartan, 40 mg, or identical placebo.Main outcomes and measuresThe primary outcome of the difference in AAA growth, assessed on core imaging laboratory-read ultrasonographic scanning, was tested with linear mixed-effects models. Other outcomes included effects on blood pressure, computed tomographic (CT)-measured AAA diameter and volume, time to AAA-related events (AAA repair or mortality due to AAA rupture), and health-related quality of life.ResultsOf 300 intended participants, 210 were enrolled and randomized to receive telmisartan (n = 107) or placebo (n = 103). Of patients included in the intention-to-treat analysis (telmisartan: n = 106, placebo: n = 101), 183 were men (88%); mean (SD) age was 73.5 (7.9) years. At 1 year, participants receiving telmisartan had mean lower systolic (8.9; 95% CI, 4.1-13.8 mm Hg; P < .001) and diastolic (7.0; 4.3-9.8 mm Hg; P < .001) blood pressure levels compared with participants receiving placebo. A total of 188 participants (91%) received at least 2 ultrasonographic scans and 133 participants (64%) had at least 2 CT scans. There was no significant difference in ultrasonographic-assessed AAA growth rates among those assigned telmisartan (1.68 mm/y) or placebo (1.78 mm/y): mean difference, -0.11 mm/y (95% CI, -0.60 to 0.38 mm/y; P = .66). Telmisartan had no significant effects on AAA growth assessed by CT-measured AAA diameter (mean difference, -0.01 mm/y; 95% CI, -0.02 to 0.01 mm/y; P = .23) or volume (mean difference, -0.02 cm3/y; 95% CI, -0.04 to 0.00 cm3/y; P = .11), AAA-related events (relative risk, 1.35; 95% CI, 0.54-3.35; P = .52), or health-related quality of life (mean difference in physical component score at 24 months, 0.4; 95% CI, 0.4-0.4; P = .80). Hypotensive symptoms (eg, syncope) were twice as common among participants receiving telmisartan compared with placebo (28 [26%] vs 13 [13%]; P = .02), but overall adverse event rates were otherwise similar for both groups.Conclusions and relevanceThis underpowered study did not show a treatment effect for telmisartan on small AAA growth. Future trials will need to ensure adequate sample size and duration of follow-up.Trial registrationsanzctr.org.au Identifier: ACTRN12611000931976; ClinicalTrials.gov Identifier: NCT01683084.

Project description:Homocysteine (Hcy) may affect the pathogenesis of abdominal aortic aneurysms (AAAs) through enhancement of proteolysis and an impaired coagulation/fibrinolysis system. Intensified haemostatic capacity may promote local proteolytic degradation of the aortic wall. This study aimed to examine the effects of Hcy on haemostatic and proteolytic processes in samples of thick and thin fragments of the ILT and underlying walls. Subjects and Methods. Thirty-six patients who underwent AAA surgery were enrolled. Aneurysm tissue sections were incubated with DL-Hcy (100 and 500 ?mol/L) in a series of experiments and analyzed for concentration/activity of proteolytic and haemostatic markers by enzyme-linked immunosorbent assay. Results. Incubation of wall underlying thin ILT segments (B) with DL-Hcy resulted in an increase of active MMP-2 levels compared to control tissue (9.54 ± 5.88 versus 7.44 ± 4.48, p=0.011). DL-Hcy also induced t-PA and plasminogen concentration increases in thin thrombus sections (B1) compared to control tissue (respectively: 1.39 ± 1.65 versus 0.84 ± 0.74, p=0.024; 11.64 ± 5.05 versus 10.34 ± 5.52, p=0.018). In contrast, wall adjacent to thick thrombus segments (A) showed decreases in MMP-2 and TF activities compared to control (respectively, 5.89 ± 3.39 versus 7.26 ± 5.49, p=0.046; 67.13 ± 72.59 versus 114.46 ± 106.29, p=0.007). In thick ILT sections (A1), DL-Hcy decreased MMP-2 activity and t-PA and plasminogen concentrations compared to control tissue (respectively, 2.53 ± 2.02 versus 3.28 ± 2.65, p=0.006; 0.67 ± 0.57 versus 0.96 ± 0.91, p=0.021; 9.25 ± 4.59 versus 12.63 ± 9.56, p=0.017). In addition, analysis revealed positive correlations at all sites between activities/concentrations of MMP-2, TF, and PAI-1 measured in control tissues and after incubation with DL-Hcy. Conclusions. These data indicate the potential for excess Hcy to enhance damage of arterial wall in thinner AAA segments as a result of the increased activity of MMP-2 and fibrinolytic factors.

Dataset Information

Fibrinolytic PLGA nanoparticles for slow clot lysis within abdominal aortic aneurysms attenuate proteolytic loss of vascular elastic matrix.

Publications

Fibrinolytic PLGA nanoparticles for slow clot lysis within abdominal aortic aneurysms attenuate proteolytic loss of vascular elastic matrix.

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