Attenuation of Maladaptive Responses in Aortic Adventitial Fibroblasts through Stimuli‐Triggered siRNA Release from Lipid–Polymer Nanocomplexes. Issue 8 (20th July 2017)

• Record Type: Journal Article
• Authors: Greco, Chad T.; Akins, Robert E.; Epps, Thomas H.; Sullivan, Millicent O.
• Is Part Of: Advanced biosystems. Volume 1 :Issue 8 (2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-07-20
• Subjects: block copolymers -- bypass grafts -- cardiovascular diseases -- myofibroblasts -- photoresponsive -- polyplexes -- TGF‐β1; Biological systems -- Periodicals; Biotechnology -- Periodicals; Bioengineering -- Periodicals; Biomedical engineering -- Periodicals; Biological Science Disciplines; Periodicals; Periodicals; 660.6
• DOI: 10.1002/adbi.201700099
• Languages: English
• ISSNs: 2366-7478

Abstract

Abstract : Lipid–siRNA assemblies are modified with photoresponsive polymers to enable spatiotemporally controlled silencing of interleukin 1 beta (IL1β) and cadherin 11 (CDH11), two genes that are essential drivers of maladaptive responses in human aortic adventitial fibroblasts. These hybrid nanocomplexes address the critical challenge of locally mitigating fibrotic actions that lead to the high rates of vascular graft failures. In particular, the lipid–polymer formulations provide potent silencing of IL1β and CDH11 that is precisely modulated by a photorelease stimulus. Moreover, a dynamic modeling framework is used to design a multidose siRNA regimen that sustains knockdown of both genes over clinically relevant timescales. Multidose suppression illuminates a cooperative role for IL1β and CDH11 in pathogenic adventitial remodeling and is directly linked to desirable functional outcomes. Specifically, myofibroblast differentiation and cellular proliferation, two of the primary hallmarks of fibrosis, are significantly attenuated by IL1β silencing. Meanwhile, the effects of CDH11 siRNA treatment on differentiation become more pronounced at higher cell densities, characteristic of constrictive adventitial remodeling in vivo. Thus, this work offers a unique formulation design for photoresponsive gene suppression in human primary cells and establishes a new dosing method to satisfy the critical need for local attenuation of fibrotic responses in the adventitium surrounding vascular grafts. Abstract : A lipid–polymer hybrid formulation is developed to spatiotemporally control the knockdown of interleukin 1 beta (IL1β) and cadherin 11 (CDH11), two key genes implicated in maladaptive responses of human primary adventitial fibroblasts. The combined silencing of these genes for one week completely halts differentiation and significantly reduces proliferation, which are critical goals for treating fibrotic responses in cardiovascular diseases.