Dataset Information

Attenuation of Maladaptive Responses in Aortic Adventitial Fibroblasts through Stimuli-Triggered siRNA Release from Lipid-Polymer Nanocomplexes.

ABSTRACT: Lipid-siRNA assemblies are modified with photo-responsive polymers to enable spatiotemporally-controlled silencing of interleukin 1 beta (IL1?) and cadherin 11 (CDH11), two genes that are essential drivers of maladaptive responses in human aortic adventitial fibroblasts (AoAFs). 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 IL1? and CDH11 that is precisely modulated by a photo-release stimulus. Moreover, a dynamic modeling framework is used to design a multi-dose siRNA regimen that sustains knockdown of both genes over clinically-relevant timescales. Multi-dose suppression illuminates a cooperative role for IL1? 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 IL1? 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 photo-responsive 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.

SUBMITTER: Greco CT

PROVIDER: S-EPMC5788321 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Attenuation of Maladaptive Responses in Aortic Adventitial Fibroblasts through Stimuli-Triggered siRNA Release from Lipid-Polymer Nanocomplexes.

Greco Chad T CT Akins Robert E RE Epps Thomas H TH Sullivan Millicent O MO

Advanced biosystems 20170720 8

Lipid-siRNA assemblies are modified with photo-responsive 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 (AoAFs). 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 silenc ...[more]

PMID: 29392169

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Project description:Nanoparticulate systems have shown great promise in overcoming the considerable trafficking barriers associated with systemic nucleic acid delivery, which must be addressed to unlock the full potential of technologies such as RNAi and gene editing in vivo. In addition to mediating the cytoplasmic delivery of nucleic cargo and shielding it from nuclease degradation and immunostimulation, nucleic-acid-containing nanomaterials delivered intravenously must also be stable in the bloodstream after administration to avoid toxicity and off-target delivery. To this end, the hydrophilic molecule polyethylene glycol (PEG) has been deployed in many different nanoparticle systems to prevent aggregation and recognition by the reticuloendothelial system. However, the optimal strategy for incorporating PEG into self-assembled nucleic acid delivery systems to obtain nanoparticle stability while retaining important functions such as receptor targeting and cargo activity remains unclear. In this work, we develop substantially improved formulations of tumor-penetrating nanocomplexes (TPNs), targeted self-assembled nanoparticles formulated with peptide carriers and siRNA that have been shown to mitigate tumor burden in an orthotopic model of ovarian cancer. We specifically sought to tailor TPNs for intravenous delivery by systematically comparing formulations with three different classes of modular PEG incorporation (namely PEG graft polymers, PEG lipids, and PEGylated peptide), each synthesized using straightforward bioconjugation techniques. We found that the addition of PEG lipids or PEGylated peptide carriers led to the formation of small and stable nanoparticles, but only nanoparticles formulated with PEGylated peptide carriers retained substantial activity in a gene silencing assay. In vivo, this formulation significantly decreased accumulation in off-target organs and improved initial availability in circulation compared to results from the original non-PEGylated particles. Thus, from among a set of candidate strategies, we identified TPNs with admixed PEGylated peptide carriers as the optimal formulation for systemic administration of siRNA on the basis of their performance in a battery of physicochemical and biological assays. Moreover, this optimized formulation confers pharmacologic advantages that may enable further translational development of tumor-penetrating nanocomplexes, highlighting the preclinical value of comparing formulation strategies and the relevance of this systematic approach for the development of other self-assembled nanomaterials.

Dataset Information

Attenuation of Maladaptive Responses in Aortic Adventitial Fibroblasts through Stimuli-Triggered siRNA Release from Lipid-Polymer Nanocomplexes.

Publications

Attenuation of Maladaptive Responses in Aortic Adventitial Fibroblasts through Stimuli-Triggered siRNA Release from Lipid-Polymer Nanocomplexes.

Similar Datasets

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