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  • Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice.

Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice.

Nanotechnology (2012-11-29)
Ruchit Trivedi, Elizabeth F Redente, Ashish Thakur, David W H Riches, Uday B Kompella
ABSTRACT

Our purpose was to assess sustained delivery and enhanced efficacy of pirfenidone-loaded nanoparticles after intratracheal instillation.Poly(lactide-co-glycolide) nanoparticles containing pirfenidone (NPs) were prepared and characterized. Biodistribution of NPs and solution was assessed using LC-MS after intratracheal administration in C57Bl/6 mice at 3 and 24 h and 1 week post-administration. Efficacy was tested in C57Bl/6 mice in a bleomycin-induced pulmonary fibrosis model. Mice received 10 μg pirfenidone intratracheally in solution or NPs, once a week, for 3 weeks after bleomycin administration. Drug effects were monitored on day 28. Lung hydroxyproline content, total number of cells, and numbers of macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage (BAL) were assessed. Numbers of macrophages, lymphocytes, and neutrophils were assessed in the lung as well.NPs sustained significantly higher levels of pirfenidone in the lungs and BAL at 24 h and 1 week, compared to the solution group. Pirfenidone solution and NPs significantly reduced hydroxyproline levels by 57 and 81%, respectively, compared to bleomycin alone. At the end of 4 weeks, BAL cellularity was reduced by 25.4% and 56% with solution and NP treatment, respectively. The numbers of lymphocytes and neutrophils in the BAL were also reduced by 58.9 and 82.4% for solution and 74.5% and 89.7% for NPs, respectively. The number of inflammatory macrophages in the lung was reduced by 62.8% and the number of neutrophils was reduced by 59.1% in the NP group and by 37.7% and 44.5%, respectively, in the solution group, compared to bleomycin alone.In conclusion, nanoparticles sustain lung pirfenidone delivery and enhance its anti-fibrotic efficacy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Resomer® RG 505, Poly(D,L-lactide-co-glycolide), ester terminated, Mw 54,000-69,000
Sigma-Aldrich
Pirfenidone, ≥97% (HPLC)
Sigma-Aldrich
Resomer® RG 504 H, Poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 50:50, Mw 38,000-54,000
Sigma-Aldrich
Resomer® RG 756 S, Poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 75:25, Mw 76,000-115,000
Sigma-Aldrich
Resomer® RG 858 S, Poly(D,L-lactide-co-glycolide), ester terminated, lactide:glycolide 85:15, Mw 190,000-240,000
Sigma-Aldrich
Resomer® RG 504, Poly(D,L-lactide-co-glycolide), lactide:glycolide 50:50, ester terminated, Mw 38,000-54,000
Sigma-Aldrich
Resomer® RG 503, Poly(D,L-lactide-co-glycolide), lactide:glycolide 50:50, ester terminated, Mw 24,000-38,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), ester terminated, Mw 50,000-75,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), lactide:glycolide 65:35, Mw 40,000-75,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), lactide:glycolide (75:25), mol wt 66,000-107,000
Sigma-Aldrich
Poly(D,L-lactide-co-glycolide), lactide:glycolide (50:50), mol wt 30,000-60,000
Sigma-Aldrich
Resomer® RG 752 H, Poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 75:25, Mw 4,000-15,000
Sigma-Aldrich
Resomer® RG 653 H, Poly(D,L-lactide-co-glycolide), acid terminated, Mw 24,000-38,000
Sigma-Aldrich
Resomer® RG 503 H, Poly(D,L-lactide-co-glycolide), acid terminated, lactide:glycolide 50:50, Mw 24,000-38,000
Sigma-Aldrich
Resomer® RG 502 H, Poly(D,L-lactide-co-glycolide), acid terminated, Mw 7,000-17,000
Sigma-Aldrich
Resomer® RG 502, Poly(D,L-Lactide-co-Glycolide), lactide:glycolide 50:50, ester terminated, Mw 7,000-17,000