The Nucleic Acid Scavenger Polyamidoamine Third-Generation Dendrimer Inhibits Fibroblast Activation and Granulation Tissue Contraction

Abstract

Background Pathologic cutaneous scarring affects over 40 million people worldwide and costs billions of dollars annually. Understanding mechanisms of fibroblast activation and granulation tissue contraction is the first step toward preventing pathologic scarring. The authors hypothesize that nucleic acids increase fibroblast activation and cause granulation tissue contraction and sequestration of nucleic acids by application of a nucleic acid scavenger dendrimer, polyamidoamine third-generation dendrimer, will decrease pathologic scarring. Methods In vitro experiments were performed to assess the effect of nucleic acids on pathologic scar–associated fibroblast activity. The effect of nucleic acids on cytokine production (polymerase chain reaction) and migration on mouse fibroblasts was evaluated. Immunofluorescence microscopy was used to determine the effect of nucleic acids on the differentiation of human primary fibroblasts into myofibroblasts. Using a murine model, the effect of polyamidoamine third-generation dendrimer on granulation tissue contraction was evaluated by gross and histologic parameters. Results Mouse fibroblasts stimulated with nucleic acids had increased cytokine production (i.e., transforming growth factor-β, monocyte chemotactic protein 1, interleukin-10, tumor necrosis factor-α, and interferon-γ), migration, and differentiation into myofibroblasts. Polyamidoamine third-generation dendrimer blocked cytokine production, migration, and differentiation into myofibroblasts. Using a murine model of granulation tissue contraction, polyamidoamine third-generation dendrimer decreased wound contraction and angiogenesis. Collagen deposition in polyamidoamine third-generation dendrimer–treated tissues was aligned more randomly and whorl-like compared with control tissue. Conclusions The data demonstrate that nucleic acid–stimulated fibroblast activation and granulation tissue contraction is blocked by polyamidoamine third-generation dendrimer. Sequestration of pathogen-associated molecular patterns may be an approach for preventing pathologic scarring.

Toll Like Receptors in systemic sclerosis: An emerging target

“…These CpG stimulated cells both stably expressed α-Sma and PDGFRα, a key receptor for fibrosis generation and an increased resistance to apoptosis and reduced caspase-3 levels, possibly mediated through HIF-1α expression [65]. In mouse fibroblast it was also shown that CpG stimulation leads to enhanced myofibroblasts and cytokine induction and using a wound healing model in mice it was shown that blocking the nucleic acid with a third-generation dendrimer reduced granulation tissue [66]. TLR9 gene deleted mice are protected from experimental liver fibrosis also suggesting a universal phenomenon [67].…”

“…AZD1419 is a TLR9 agonist developed by Dynavax that targets the TLR9 system to modify the immune response in allergic asthma. Another possible therapeutic is to sequester the nucleic acids and this has already been done using a third generation dendrimer that scavengers nucleic acid and this reduced granulation tissue in an animal model [66].…”

Gene therapy in wound healing using nanotechnology

“…Dendrimers on their own have also been shown to kill multidrug‐resistant pseudomonas strains and can even exert angiogenic effects in wounds 73 . Dendrimers can also serve to scavenge pathogenic molecules, like nucleic acid in pathogenic scarring processes, and decrease wound contraction and augment fibroblast activities 74 . Unlike other NPs, the evidence for the use of growth factor with dendrimers in wounds remains limited, despite favorable results of protein delivery by Dąbkowska et al 75 Additionally, as the structure of dendrimers can easily be changed by drugs, which affects biochemical performance, its clinical potential remains limited to specific drugs combinations that are inert 76 .…”

“…73 Dendrimers can also serve to scavenge pathogenic molecules, like nucleic acid in pathogenic scarring processes, and decrease wound contraction and augment fibroblast activities. 74 Unlike other NPs, the evidence for the use of growth factor with dendrimers in wounds remains limited, despite favorable results of protein delivery by Dąbkowska et al 75 Additionally, as the structure of dendrimers can easily be changed by drugs, which affects biochemical performance, its clinical potential remains limited to specific drugs combinations that are inert. 76 Nevertheless, NPs continue to show potential in improving many aspects of wound healing and will likely remain a topic of interest.…”

Polymeric drugs: Advances in the development of pharmacologically active polymers

“…Other irregular immune pathogenesis could also be overcome by the polycations, including systemic lupus erythematosus caused by binding of extracellular DNA and anti-DNA antibodies [89,90]. A recent report showed that topical administration of G3 PAMAM dendrimers could efficiently sequester nucleic acids that cause increase in fibroblast activation and granulation tissue contraction, resulting in decreased pathological scarring during wound healing [91]. In addition, the application of polycations as antithrombotic agents that rapidly remove prothrombotic nucleic acids together with other polyphosphates was also demonstrated in vivo and proposed as a novel strategy to prevent thrombosis after injury [92].…”