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


CONCLUSIONS
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.
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan. miyaji.yoshihiro.gw@rdn.daiichisankyo.co.jp
Yoshihiro
Y
Miyaji
Yuji
Y
Kasuya
Yoshitake
Y
Furuta
Atsushi
A
Kurihara
Masayuki
M
Takahashi
Ken-Ichi
K
Ogawara
Takashi
T
Izumi
Osamu
O
Okazaki
Kazutaka
K
Higaki
D061605:Administration, Intravenous; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D008298:Maleates / Q000008:administration & dosage / Q000737:chemistry; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D010052:Ovariectomy / Q000379:methods; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D004337:Drug Carriers; D008298:Maleates; D053244:Osteoprotegerin; D011108:Polymers; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C008311:maleamic acid