Polysaccharide nanogel delivery of a TNF-alpha and RANKL antagonist peptide allows systemic prevention of bone loss.
We report here a nanogel-mediated peptide drug delivery system. Low stability is a major drawback towards clinical application of peptide drugs. The W9-peptide, a TNF-alpha and RANKL antagonist, was used as a model for testing the feasibility of cholesterol-bearing pullulan (CHP)-nanogel as the drug delivery system. We found CHP-nanogel could form complex with the W9-peptide and prevents its aggregation in vitro. Murine bone resorption model using low dietary calcium was used to investigate the in vivo effect. Two-time-injection of 24 mg/kg W9-peptide per day with or without CHP-nanogel was given for 7 days. Thereafter, radiological, and histological assessments were performed. The injections of the W9-peptide (24 mg/kg) with CHP-nanogel prevented the reduction in bone mineral density whereas the same dose without CHP-nanogel could not show any inhibitory effect. Histomorphometric analysis of tibiae showed significant decrease of osteoclast number and surface in CHP-W9 complex treated group and the levels of urinary deoxypyridinoline reflected these decrease of bone resorption parameters. Taken together these data shows that CHP-nanogel worked as a suitable carrier for the W9-peptide and it prevented aggregation and increased the stability of the W9-peptide. This study reveals the feasibility of CHP-nanogel-mediated peptide delivery in preventing bone resorption in vivo.
Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
Neil
N
Alles
Niroshani S
NS
Soysa
M D Anower
MD
Hussain
Nobuyoshi
N
Tomomatsu
Hiroaki
H
Saito
Roland
R
Baron
Nobuyuki
N
Morimoto
Kazuhiro
K
Aoki
Kazunari
K
Akiyoshi
Keiichi
K
Ohya
D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control*; D002118:Calcium / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036103:Nanotechnology; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology; D011134:Polysaccharides / Q000032:analysis*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D010455:Peptides; D011134:Polysaccharides; D053245:RANK Ligand; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium