Intranasal Delivery of PEGylated Salmon Calcitonins: Hypocalcemic Effects in Rats
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- 作者：K. C. Lee ; M. -O. Park ; D. H. Na ; Y. S. Youn ; S. D. Lee ; S. D. Yoo ; H. S. Lee and P. P. DeLuca
- 关键词：Calcitonin ; Intranasal delivery ; Polyethylene glycol ; PEGylation ; Hypocalcemic effect
- 刊名：Calcified Tissue International
- 出版年：2003
- 出版时间：December 2003
- 年：2003
- 卷：73
- 期：6
- 页码：545-549
- 全文大小：127 KB
文摘
To evaluate the hypocalcemic effect of polyethylene gtycol-conjugated salmon calcitonins (PEG-sCT) in rats, mono-PEGylated sCTs (mono-PEG-sCTs) and unmodified sCT were administered via the intranasal route and serum calcium levels were measured by colorimetric assay using o-cresolphthalein. Mono-PEG-sCTs were prepared with different sizes of succinimidyl succinate monomethoxy PEG molecules (PEG2K, PEG5K, PEG12K) and characterized by HPLC and MALDI-TOF mass spectrometry. Nasal instillation of mono-PEG2K-sCT at a dose of 2 IU/kg resulted in sustained reduction in serum calcium levels over 8 hr, with a maximum reduction ( % maxd) of 13 % after 6 hr of application. Whereas unmodified sCT showed a transient decrease in serum calcium levels with the maximum reduction (5 % ) observed after 30 min of administration. The overall reductions in serum calcium levels expressed as the net change in AUC relative to control in 8 hr were 11.9 ± 0.2, 4.6 ± 0.7, and 2.6 ± 0.7 % for mono-PEG2K-, mono-PEG5K-, and mono-PEG12K-sCT, respectively, compared to 3.2 ± 0.6 % for unmodified sCT. The relative bioavailability of nasally administered 2 IU/kg of mono-PEG2K-sCT was approximately 4-fold higher than nasally administrated unmodified sCT, and the absolute bioavailability was approximately 91 % of intravenously injected sCT in 8 hr. It can be concluded that the intranasal absorption of mono-PEG-sCTs was inversely related to the molecular weights of the PEG attached. Of the PEGylated sCTs examined, mono-PEG2K-sCT showed the most pronounced hypocalcemic effect. Therefore the intranasal application would probably be an alternative route of administration for mono-PEG-sCTs in achieving sustained calcium-lowering effects.