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PEGylation of Octreotide: II. Effect of N-terminal Mono-PEGylation on Biological Activity and Pharmacokinetics

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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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Authors and Affiliations

  1. College of Pharmacy, Kyungsung University, Busan, South Korea

    Dong Hee Na & Patrick P. DeLuca

  2. Drug Targeting Laboratory, College of Pharmacy, SungKyunKwan University, Suwon City, South Korea

    Kang Choon Lee

  3. University of Kentucky College of Pharmacy, Lexington, Kentucky, USA

    Patrick P. DeLuca

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  1. Dong Hee Na
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  2. Kang Choon Lee
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  3. Patrick P. DeLuca
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Correspondence to Patrick P. DeLuca.

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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

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