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Reversal of elastin calcification and aneurysm in a rat model using dual targeted therapy with EDTA- and
PGG-loaded nanoparticles
Nasim Nosoudi, Aniqa Chowdhury, Steven Siclari, Saketh Karamched, Vaideesh Parasaram, Joe Parrish,
Narendra Vyavahare1
1
Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
Background and Objective: Degeneration of elastic lamina and vascular calcification are common features of vascular
pathology such as aortic aneurysms. We tested whether dual therapy with targeted nanoparticles (NPs) can remove mineral
deposits (by delivery a chelating agent, ethylene diamine tetraacetic acid (EDTA)) and restore elastic lamina (by delivery
of polyphenol, pentagalloyl glucose (PGG)) to reverse moderately developed aneurysmal disease.
Methods: Albumin nanoparticles (NPs) with a surface-conjugated elastin-specific antibody that targets only degraded
elastic lamina and that were loaded with either EDTA or PGG were prepared. The calcium chloride-induced rat model of
abdominal aortic aneurysm was used 1. Animals were divided into four groups. A moderate stage aneurysm and calcification
were allowed to develop for four weeks, and one group of animals received tail vein injection of EDTA NPs (twice a week).
Two weeks after EDTA therapy (6 weeks total), these rats received PGG-loaded NPs (once every two weeks). In the other
three groups, aneurysm was allowed to progress for six weeks. At that point, one group received blank NPs, and one group
received PGG NPs (once every two weeks). As a control, one group received an MMP inhibitor, BB-94-loaded NPs (once
a week). After 12 weeks, rats were euthanized, and disease development, calcification, and elastic lamina restoration was
studied.
Results and Discussion: When EL-NP-PGG or EL-NP-EDTA+EL-NPPGG NPs were injected; a significant suppression of aortic external
diameter change was observed after 12 weeks. NP delivery of BB94 (ELNP-BB94) showed no reversal of aortic external diameter (Figure 1).
Moreover, EDTA followed by PGG NP delivery led to reduction in
macrophage recruitment, MMP activity, elastin degradation and
calcification in the aorta as compared to control blank, BB-94, and PGG
NP delivery alone. It restored vascular elastic lamina and improved
vascular function as observed by improvement in circumferential strain.
Conclusions: Dual targeted therapy may be an attractive option to
remove mineral deposits and restore healthy arterial structures in
moderately developed aneurysm.
Figure 1: (A) diameter change in different groups of
treatment and control. (B) representative images of aorta
at the time of euthanasia. *, P < 0.05 represents statistical
significance, Tukey's test (pairwise comparison). #, P <
0.05, Exact permutation test. (n=6).
References:
1. Gertz, S. David, Adi Kurgan, and Daniel Eisenberg. "Aneurysm of the rabbit common carotid artery induced by
periarterial application of calcium chloride in vivo." Journal of Clinical Investigation 81.3 (1988): 649.