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Functional Nano-Drug Conjugates for Wall Repair in Abdominal Aortic Aneurysms.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Functional Nano-Drug Conjugates for Wall Repair in Abdominal Aortic Aneurysms.
Author:	Bastola, Suraj.
Published:	Ann Arbor : ProQuest Dissertations & Theses, 2024
Description:	233 p.
Notes:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Notes:	Advisor: Ramamurthi, Anand.
Contained By:	Dissertations Abstracts International85-07B.
Subject:	Bioengineering.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30815119
ISBN:	9798381377781

Functional Nano-Drug Conjugates for Wall Repair in Abdominal Aortic Aneurysms.
Bastola, Suraj.

Functional Nano-Drug Conjugates for Wall Repair in Abdominal Aortic Aneurysms. - Ann Arbor : ProQuest Dissertations & Theses, 2024 - 233 p.

Source: Dissertations Abstracts International, Volume: 85-07, Section: B.

Thesis (Ph.D.)--Lehigh University, 2024.

This item must not be sold to any third party vendors.

Abdominal aortic aneurysms (AAAs) are localized expansion of the abdominal aorta, characterized by chronic proteolytic breakdown of the structural elastic matrix (elastin and collagen) by matrix metalloproteases (MMPs). This expansion culminates to a fatal pre-rupture stage necessitating immediate surgical intervention but is often associated with significant risks. Challenges in regenerative repair of the elastic matrix include poor electrogenicity of diseased or adult smooth muscle cells, intricate pathophysiology, and reduced nitric oxide (NO) levels due to endothelial dysfunction. The pro-inflammatory milieu of AAAs further complicates this process, emphasizing the urgent need for alternative treatment strategies that provide continuous stimuli promoting elastogenesis and counteracting proteolytic breakdown of the elastic matrix. Our previous study, where we demonstrated the exogenous activation of abdominal aortic smooth muscle cells (aHASMCs) with the nitric oxide (NO) donor drug, sodium nitroprusside (SNP), resulted in increased NO bioavailability and enhanced regenerative repair of the elastic matrix in vitro. However, translating this success to real-time AAA scenarios faces challenges when attempting oral SNP delivery, given the short half-life of released NO and risk of degradation by biological and biochemical barriers, ultimately diminishing drug bioavailability to the target tissue. To tackle these challenges, this thesis introduces lipid nanoparticle charge grafts (LCGs) with the goal of facilitating a slow, long-term release of SNP upon it periadventitial placement, providing a sustained and continuous stimulus for regenerative repair efforts in the AAA wall. The thesis presents strong evidence supporting LCGs as an effective treatment option in in-vitro aHASMC cultures, complemented by a limited proof of concept in an ex-vivo AAA model. This ex-vivo model involves a decellularized porcine carotid artery recellularized with aHASMCs, showcasing LCGs' proficiency in elastin regeneration and inhibition of proteolytic activities of MMP2. The thesis accentuates the potential of LCGs in addressing the challenges of regenerative repair within the complex AAA environment, marking a significant stride toward more effective treatments for this life-threatening condition.The primary goal of this thesis was to assess the feasibility of an alternative treatment strategy aimed at impeding or reversing AAA pathophysiology. This was achieved by demonstrating the regenerative potential of SNP and SNP-releasing LCGs through in-vitro and ex-vivo AAA models. The study sought to elucidate the underlying mechanisms behind these regenerative capabilities. Our in-vitro results demonstrated that exogenous delivery of SNP exhibits the ability to upregulate elastic matrix assembly, crosslinking, and maturation while concurrently inhibiting matrix metalloproteinases (particularly MMP2) through NO-mediated mitogen-activated protein kinase (MAPK) inhibition. The utilization of LCGs demonstrates a significant downregulation of MMP2, coupled with an upregulation of key proteins crucial for ECM maintenance (LOX, elastin, TIMP2 and TIMP4) and vascular health. In an ex-vivo decellularized porcine carotid artery (dPCA) AAA model, recellularized with aHASMCs, LCGs exhibit cytocompatibility, allowing cell growth, and evidence of anti-proteolysis (MMP2 downregulation) and elastic matrix neoassembly (upregulated elastin). The sustained release behavior of SNP from LCGs, as demonstrated through the Korsmeyer-Peppas model, suggests controlled and prolonged therapeutic SNP delivery. Addressing the short half-life of NO through LCGs presents an opportunity for more sustained and effective ECM repair. This study introduces a novel strategy for LCG development, successfully conjugating bLNPs onto bPCL meshes to create efficient functional nanodrug conjugates for localized SNP delivery. The promising results signify a significant advancement towards more effective treatments for AAA, offering insights into the dynamic role of NO in maintaining vascular health and ECM homeostasis.

ISBN: 9798381377781Subjects--Topical Terms:

229635
Bioengineering.
Subjects--Index Terms:

Abdominal aortic aneurysms

Functional Nano-Drug Conjugates for Wall Repair in Abdominal Aortic Aneurysms.
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300 $a 233 p.
500 $a Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
500 $a Advisor: Ramamurthi, Anand.
502 $a Thesis (Ph.D.)--Lehigh University, 2024.
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520 $a Abdominal aortic aneurysms (AAAs) are localized expansion of the abdominal aorta, characterized by chronic proteolytic breakdown of the structural elastic matrix (elastin and collagen) by matrix metalloproteases (MMPs). This expansion culminates to a fatal pre-rupture stage necessitating immediate surgical intervention but is often associated with significant risks. Challenges in regenerative repair of the elastic matrix include poor electrogenicity of diseased or adult smooth muscle cells, intricate pathophysiology, and reduced nitric oxide (NO) levels due to endothelial dysfunction. The pro-inflammatory milieu of AAAs further complicates this process, emphasizing the urgent need for alternative treatment strategies that provide continuous stimuli promoting elastogenesis and counteracting proteolytic breakdown of the elastic matrix. Our previous study, where we demonstrated the exogenous activation of abdominal aortic smooth muscle cells (aHASMCs) with the nitric oxide (NO) donor drug, sodium nitroprusside (SNP), resulted in increased NO bioavailability and enhanced regenerative repair of the elastic matrix in vitro. However, translating this success to real-time AAA scenarios faces challenges when attempting oral SNP delivery, given the short half-life of released NO and risk of degradation by biological and biochemical barriers, ultimately diminishing drug bioavailability to the target tissue. To tackle these challenges, this thesis introduces lipid nanoparticle charge grafts (LCGs) with the goal of facilitating a slow, long-term release of SNP upon it periadventitial placement, providing a sustained and continuous stimulus for regenerative repair efforts in the AAA wall. The thesis presents strong evidence supporting LCGs as an effective treatment option in in-vitro aHASMC cultures, complemented by a limited proof of concept in an ex-vivo AAA model. This ex-vivo model involves a decellularized porcine carotid artery recellularized with aHASMCs, showcasing LCGs' proficiency in elastin regeneration and inhibition of proteolytic activities of MMP2. The thesis accentuates the potential of LCGs in addressing the challenges of regenerative repair within the complex AAA environment, marking a significant stride toward more effective treatments for this life-threatening condition.The primary goal of this thesis was to assess the feasibility of an alternative treatment strategy aimed at impeding or reversing AAA pathophysiology. This was achieved by demonstrating the regenerative potential of SNP and SNP-releasing LCGs through in-vitro and ex-vivo AAA models. The study sought to elucidate the underlying mechanisms behind these regenerative capabilities. Our in-vitro results demonstrated that exogenous delivery of SNP exhibits the ability to upregulate elastic matrix assembly, crosslinking, and maturation while concurrently inhibiting matrix metalloproteinases (particularly MMP2) through NO-mediated mitogen-activated protein kinase (MAPK) inhibition. The utilization of LCGs demonstrates a significant downregulation of MMP2, coupled with an upregulation of key proteins crucial for ECM maintenance (LOX, elastin, TIMP2 and TIMP4) and vascular health. In an ex-vivo decellularized porcine carotid artery (dPCA) AAA model, recellularized with aHASMCs, LCGs exhibit cytocompatibility, allowing cell growth, and evidence of anti-proteolysis (MMP2 downregulation) and elastic matrix neoassembly (upregulated elastin). The sustained release behavior of SNP from LCGs, as demonstrated through the Korsmeyer-Peppas model, suggests controlled and prolonged therapeutic SNP delivery. Addressing the short half-life of NO through LCGs presents an opportunity for more sustained and effective ECM repair. This study introduces a novel strategy for LCG development, successfully conjugating bLNPs onto bPCL meshes to create efficient functional nanodrug conjugates for localized SNP delivery. The promising results signify a significant advancement towards more effective treatments for AAA, offering insights into the dynamic role of NO in maintaining vascular health and ECM homeostasis.
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