Abstract
Purpose.
To determine the optimal polyethylene glycol (PEG)-conjugate of octreotide by evaluating the effects of PEGylation chemistry on the biological activity and pharmacokinetic properties.
Methods.
Octreotide was chemically modified by reaction with succinimidyl propionate monomethoxy PEG (SPA-mPEG, molecular weight 2000) or succinimidyl butyraldehyde-mPEG (ALD-mPEG, molecular weight 2000 and 5000). The structural conformation of PEG-octreotides was evaluated by circular dichroism (CD), the biological activity was assessed by measuring the decrease of serum insulin-like growth factor-I levels in rats, and a pharmacokinetic study was performed after subcutaneous administration in rats. The stability against acylation was investigated with poly(d,l-lactide-co-glycolide) (PLGA).
Results.
ALD-mPEG was site-specific in PEGylating octreotide at the N-terminus. The mono-PEG-octreotides prepared with ALD-mPEG (mono-ALDPEG-octreotide), which alkyl bond preserves the amine’s positive charge, showed complete preservation of biological activity, whereas the PEG-octreotides prepared with SPA-mPEG showed lower activity. In the CD analysis, the spectra of the mono-ALDPEG-octreotides were nearly superimposable with that of native octreotide. The mono-ALDPEG-5K-octreotide showed significantly improved pharmacokinetic properties compared with mono-ALDPEG-2K-octreotide as well as native octreotide. Both mono-ALDPEG-2K- and mono-ALDPEG-5K-octreotides were stable against acylation by degrading PLGA.
Conclusions.
The mono-PEGylation of octreotide at N-terminus with ALD-mPEG produced a conjugate that is biologically and structurally active and stable against acylation by PLGA, and therefore it may serve as a candidate for somatostatin microsphere formulations.
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Na, D., Lee, K. & DeLuca, P. PEGylation of Octreotide: II. Effect of N-terminal Mono-PEGylation on Biological Activity and Pharmacokinetics. Pharm Res 22, 743–749 (2005). https://doi.org/10.1007/s11095-005-2590-y
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DOI: https://doi.org/10.1007/s11095-005-2590-y