- Inhibiting the activation of myofibroblasts, a predominant source of collagen and pro-fibrotic mediators in idiopathic pulmonary fibrosis, is a potential strategy for preventing the progression of fibrosis or even reversing established disease
- One way myofibroblast activation occurs is through activation of the Rho/MRTF/SRF pathway, but global inhibition of that pathway could lead to toxicity such as impairment of normal wound healing and tissue integrity
- This study tested nanoparticles loaded with a drug that inhibits the Rho/MRTF/SRF pathway, targeted to myofibroblasts using a peptide recognized by the angiotensin II type 2 receptor, which is upregulated on myofibroblasts in fibrotic lung tissue
- In a mouse model of pulmonary fibrosis induced by intratracheal delivery of bleomycin, one dose of the drug-loaded targeted nanoparticles was nontoxic and accumulated in lung myofibroblasts, reducing fibrosis by 15% compared with two control groups
- The findings have broad implications, as they suggest targeted nanoparticles could allow safe delivery of other drugs to other pathogenic cell types while limiting effects on normal cells
Dysregulated wound repair after lung injury is believed to be a critical component of the pathogenesis of idiopathic pulmonary fibrosis. Lung fibroblasts are activated and recruited to the site of injury at the alveolar epithelium, where they transition into myofibroblasts, the predominant source of collagen and pro-fibrotic mediators.
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In addition, myofibroblasts are highly contractile and can alter lung biomechanical properties through tissue contraction. However, myofibroblasts don't play a significant role in normal tissue homeostasis, so inhibiting their activation is a potential therapeutic strategy for preventing the progression of fibrosis or even reversing established disease.
Rachel S. Knipe, MD, and Benjamin D. Medoff, MD, both of the Division of Pulmonary and Critical Care Medicine and the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital, Jason R. McCarthy, PhD, formerly at Mass General, and colleagues used an innovative approach to accomplish that goal. To improve upon existing validated targets which have been limited by toxicity, they developed nanoparticles for the precision delivery of a drug already known to block myofibroblast activation. In a mouse model, they demonstrated the potential to target signaling pathways in a cell-specific manner, allowing increased efficacy without apparent off-target effects. Their report appears in the American Journal of Physiology—Lung Cellular and Molecular Physiology.
One of the ways myofibroblast activation occurs is through activation of the Rho/MRTF/SRF pathway. However, this pathway is also an important homeostatic signaling mechanism for many cells, so global inhibition could lead to impaired wound healing and disrupted tissue integrity. Cell-specific targeting would be appealing if it could target myofibroblasts with reduced collateral damage.
This study tested nanoparticles loaded with CCG-1423, a Rho/MTRF/SRF pathway inhibitor previously shown to block myofibroblast activation in vitro. To accomplish cell-specific uptake of the drug-loaded particles, the team used a peptide-based ligand recognized by the angiotensin II type 2 receptor (AGTR2).
Expression of that receptor is upregulated in the lungs of patients with idiopathic pulmonary fibrosis, on myofibroblasts, and not on quiescent fibroblasts, which suggests AGTR2 is an excellent target.
In Vivo Model
On day 10 after bleomycin-induced lung injury, mice received a single intravenous injection of CCG-1423 formulated in targeted nanoparticles at a dose of 3 mg/kg, which would ordinarily be subtherapeutic. Control groups received targeted nanoparticles without CCG-1423 or nanoparticles that contained CCG-1423 but were not targeted to AGTR2.
After organ harvest on day 14:
- Only targeted nanoparticles (with or without CCG-1423) were found within the lung, and the percentage of uptake in the lung was higher in fibroblasts than in hematopoietic, endothelial, or epithelial cells
- No significant uptake of non-targeted nanoparticles was seen in any organs
- Fibrosis was reduced by 15% in mice that received targeted nanoparticles containing CCG-1423, compared with the two control groups
- A 3 mg/kg dose of free drug had no effect on lung fibrosis
In a separate experiment, targeted nanoparticles containing CCG-1423 had a protective effect on mouse survival over 28 days of observation compared with the control groups, although the differences weren't statistically significant.
These results suggest that targeted nanoparticles may allow the safe delivery of drugs to specific pathogenic cell types while limiting effects on normal cells. The findings are an important breakthrough because nanoparticle drug delivery would expand potential uses for drugs in development that might otherwise have different and undesirable downstream consequences in different cell types.
Refer a patient to the Division of Pulmonary and Critical Care Medicine