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.
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.
Authors: Dong Hee Na; Yu Seok Youn; Sang Deuk Lee; Mi-Won Son; Won-Bae Kim; Patrick P DeLuca; Kang Choon Lee Journal: J Control Release Date: 2003-10-30 Impact factor: 9.776
Authors: E Pohl; A Heine; G M Sheldrick; Z Dauter; K S Wilson; J Kallen; W Huber; P J Pfäffli Journal: Acta Crystallogr D Biol Crystallogr Date: 1995-01-01
Authors: Andreas M Sophocleous; Kashappa-Goud H Desai; J Maxwell Mazzara; Ling Tong; Ji-Xin Cheng; Karl F Olsen; Steven P Schwendeman Journal: J Control Release Date: 2013-09-08 Impact factor: 9.776
Authors: Ryan G Soderquist; Erin D Milligan; Evan M Sloane; Jacqueline A Harrison; Klarika K Douvas; Joseph M Potter; Travis S Hughes; Raymond A Chavez; Kirk Johnson; Linda R Watkins; Melissa J Mahoney Journal: J Biomed Mater Res A Date: 2009-12 Impact factor: 4.396
Authors: Ryan G Soderquist; Erin D Milligan; Jacqueline A Harrison; Raymond A Chavez; Kirk W Johnson; Linda R Watkins; Melissa J Mahoney Journal: J Biomed Mater Res A Date: 2010-06-01 Impact factor: 4.396