Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats

Yoshihiro Miyaji; Yuji Kasuya; Yoshitake Furuta; Atsushi Kurihara; Masayuki Takahashi; Ken-ichi Ogawara; Takashi Izumi; Osamu Okazaki; Kazutaka Higaki

doi:10.1007/s11095-012-0807-4

Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats

Yoshihiro Miyaji, Yuji Kasuya, Yoshitake Furuta, Atsushi Kurihara, Masayuki Takahashi, Ken-ichi Ogawara, Takashi Izumi, Osamu Okazaki, Kazutaka Higaki

Research output: Contribution to journal › Article › peer-review

5 Citations (Scopus)

Abstract

Purpose: Recombinant osteoprotegerin (OPG) has been proven to be useful for treating various bone disorders such as osteoporosis. To improve its in vivo pharmacological effect, OPG was conjugated to novel comb-shaped co-polymers of polyethylene glycol (PEG) allylmethylether and maleamic acid (poly(PEG), 5 kDa). Biodistribution and bioactivity were evaluated. Methods: OPG was conjugated via lysine to poly(PEG) and to linear PEG (0.5 kDa and 5 kDa). Poly(PEG)-OPG was compared with linear PEG0.5k-OPG and PEG5k-OPG in terms of in vitro and in vivo efficacy and bone distribution. Results: The in vitro receptor binding study showed that poly(PEG)-OPG could be the most bioactive among the three PEG-OPG derivatives. Pharmacokinetic studies in ovariectomized (OVX) rats showed that serum half-life and AUC of poly(PEG)-OPG were comparable with those of linear PEG-OPG derivatives. For in vivo pharmacological effect, poly(PEG)-OPG showed the strongest inhibitory effect on bone resorption activity in OVX rats. Poly(PEG)-OPG demonstrated enhanced bone marrow distribution with higher selectivity than linear PEG5k-OPG. Conclusion: Poly(PEG) modification could provide longer residence time in serum and higher bone-marrow specific delivery of OPG, leading to a higher in vivo pharmacological effect.

Original language	English
Pages (from-to)	3143-3155
Number of pages	13
Journal	Pharmaceutical research
Volume	29
Issue number	11
DOIs	https://doi.org/10.1007/s11095-012-0807-4
Publication status	Published - Nov 1 2012

Keywords

PEGylation
accelerator mass spectrometry
bone marrow distribution
drug delivery
osteoporosis

ASJC Scopus subject areas

Biotechnology
Molecular Medicine
Pharmacology
Pharmaceutical Science
Organic Chemistry
Pharmacology (medical)

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10.1007/s11095-012-0807-4

Cite this

Miyaji, Y., Kasuya, Y., Furuta, Y., Kurihara, A., Takahashi, M., Ogawara, K., Izumi, T., Okazaki, O., & Higaki, K. (2012). Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats. Pharmaceutical research, 29(11), 3143-3155. https://doi.org/10.1007/s11095-012-0807-4

Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats. / Miyaji, Yoshihiro; Kasuya, Yuji; Furuta, Yoshitake et al.
In: Pharmaceutical research, Vol. 29, No. 11, 01.11.2012, p. 3143-3155.

Research output: Contribution to journal › Article › peer-review

Miyaji, Y, Kasuya, Y, Furuta, Y, Kurihara, A, Takahashi, M, Ogawara, K, Izumi, T, Okazaki, O & Higaki, K 2012, 'Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats', Pharmaceutical research, vol. 29, no. 11, pp. 3143-3155. https://doi.org/10.1007/s11095-012-0807-4

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abstract = "Purpose: Recombinant osteoprotegerin (OPG) has been proven to be useful for treating various bone disorders such as osteoporosis. To improve its in vivo pharmacological effect, OPG was conjugated to novel comb-shaped co-polymers of polyethylene glycol (PEG) allylmethylether and maleamic acid (poly(PEG), 5 kDa). Biodistribution and bioactivity were evaluated. Methods: OPG was conjugated via lysine to poly(PEG) and to linear PEG (0.5 kDa and 5 kDa). Poly(PEG)-OPG was compared with linear PEG0.5k-OPG and PEG5k-OPG in terms of in vitro and in vivo efficacy and bone distribution. Results: The in vitro receptor binding study showed that poly(PEG)-OPG could be the most bioactive among the three PEG-OPG derivatives. Pharmacokinetic studies in ovariectomized (OVX) rats showed that serum half-life and AUC of poly(PEG)-OPG were comparable with those of linear PEG-OPG derivatives. For in vivo pharmacological effect, poly(PEG)-OPG showed the strongest inhibitory effect on bone resorption activity in OVX rats. Poly(PEG)-OPG demonstrated enhanced bone marrow distribution with higher selectivity than linear PEG5k-OPG. Conclusion: Poly(PEG) modification could provide longer residence time in serum and higher bone-marrow specific delivery of OPG, leading to a higher in vivo pharmacological effect.",

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author = "Yoshihiro Miyaji and Yuji Kasuya and Yoshitake Furuta and Atsushi Kurihara and Masayuki Takahashi and Ken-ichi Ogawara and Takashi Izumi and Osamu Okazaki and Kazutaka Higaki",

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AU - Miyaji, Yoshihiro

AU - Kasuya, Yuji

AU - Furuta, Yoshitake

AU - Kurihara, Atsushi

AU - Takahashi, Masayuki

AU - Ogawara, Ken-ichi

AU - Izumi, Takashi

AU - Okazaki, Osamu

AU - Higaki, Kazutaka

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N2 - Purpose: Recombinant osteoprotegerin (OPG) has been proven to be useful for treating various bone disorders such as osteoporosis. To improve its in vivo pharmacological effect, OPG was conjugated to novel comb-shaped co-polymers of polyethylene glycol (PEG) allylmethylether and maleamic acid (poly(PEG), 5 kDa). Biodistribution and bioactivity were evaluated. Methods: OPG was conjugated via lysine to poly(PEG) and to linear PEG (0.5 kDa and 5 kDa). Poly(PEG)-OPG was compared with linear PEG0.5k-OPG and PEG5k-OPG in terms of in vitro and in vivo efficacy and bone distribution. Results: The in vitro receptor binding study showed that poly(PEG)-OPG could be the most bioactive among the three PEG-OPG derivatives. Pharmacokinetic studies in ovariectomized (OVX) rats showed that serum half-life and AUC of poly(PEG)-OPG were comparable with those of linear PEG-OPG derivatives. For in vivo pharmacological effect, poly(PEG)-OPG showed the strongest inhibitory effect on bone resorption activity in OVX rats. Poly(PEG)-OPG demonstrated enhanced bone marrow distribution with higher selectivity than linear PEG5k-OPG. Conclusion: Poly(PEG) modification could provide longer residence time in serum and higher bone-marrow specific delivery of OPG, leading to a higher in vivo pharmacological effect.

AB - Purpose: Recombinant osteoprotegerin (OPG) has been proven to be useful for treating various bone disorders such as osteoporosis. To improve its in vivo pharmacological effect, OPG was conjugated to novel comb-shaped co-polymers of polyethylene glycol (PEG) allylmethylether and maleamic acid (poly(PEG), 5 kDa). Biodistribution and bioactivity were evaluated. Methods: OPG was conjugated via lysine to poly(PEG) and to linear PEG (0.5 kDa and 5 kDa). Poly(PEG)-OPG was compared with linear PEG0.5k-OPG and PEG5k-OPG in terms of in vitro and in vivo efficacy and bone distribution. Results: The in vitro receptor binding study showed that poly(PEG)-OPG could be the most bioactive among the three PEG-OPG derivatives. Pharmacokinetic studies in ovariectomized (OVX) rats showed that serum half-life and AUC of poly(PEG)-OPG were comparable with those of linear PEG-OPG derivatives. For in vivo pharmacological effect, poly(PEG)-OPG showed the strongest inhibitory effect on bone resorption activity in OVX rats. Poly(PEG)-OPG demonstrated enhanced bone marrow distribution with higher selectivity than linear PEG5k-OPG. Conclusion: Poly(PEG) modification could provide longer residence time in serum and higher bone-marrow specific delivery of OPG, leading to a higher in vivo pharmacological effect.

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Novel comb-shaped PEG modification enhances the osteoclastic inhibitory effect and bone delivery of osteoprotegerin after intravenous administration in ovariectomized rats

Abstract

Keywords

ASJC Scopus subject areas

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