PEGylation of octreotide: II. Effect of N-terminal mono-PEGylation on biological activity and pharmacokinetics.
OBJECTIVE
: 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.
Na
Dong Hee
DH
College of Pharmacy, Kyungsung University, Busan, South Korea.
Lee
Kang Choon
KC
DeLuca
Patrick P
PP
D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002942:Circular Dichroism / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006207:Half-Life; D007279:Injections, Subcutaneous; D019344:Lactic Acid / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D015282:Octreotide / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods
D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D015282:Octreotide