TY - JOUR
T1 - Polysaccharide nanogel delivery of a TNF-α and RANKL antagonist peptide allows systemic prevention of bone loss
AU - Alles, Neil
AU - Soysa, Niroshani S.
AU - Hussain, MD Anower
AU - Tomomatsu, Nobuyoshi
AU - Saito, Hiroaki
AU - Baron, Roland
AU - Morimoto, Nobuyuki
AU - Aoki, Kazuhiro
AU - Akiyoshi, Kazunari
AU - Ohya, Keiichi
N1 - Funding Information:
We thank Dr. Ikuo Morita and Dr. Masako Akiyama (Department of Cellular Physiological Chemistry, Tokyo Medical and Dental University, Tokyo Japan) for the useful discussion on the statistical analyses in the present study. This study was supported by the grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan, to, K.A. (19390472) and K.O. (19390471).
PY - 2009/5/12
Y1 - 2009/5/12
N2 - 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-α 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.
AB - 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-α 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.
KW - Aggregation
KW - Cholesterol-bearing pullulan
KW - Drug delivery system
KW - Nanogel
KW - Peptide drugs
KW - Stability
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U2 - 10.1016/j.ejps.2009.01.002
DO - 10.1016/j.ejps.2009.01.002
M3 - Article
C2 - 19429414
AN - SCOPUS:62649098185
VL - 37
SP - 83
EP - 88
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
SN - 0928-0987
IS - 2
ER -