Document Detail

Improved intrapulmonary delivery of site-specific PEGylated salmon calcitonin: optimization by PEG size selection.
MedLine Citation:
PMID:  18023905     Owner:  NLM     Status:  MEDLINE    
The purpose of this study was to demonstrate the biological potentials of PEGylated salmon calcitonin (PEG-sCT) derivatives administered intratracheally and their dependences on PEG Mw (1, 2, 5 kDa). Initially, three different PEG-sCT derivatives were site-specifically synthesized by attaching PEG to the Lys(18)-amine. In an attempt to examine the pulmonary feasibilities of these derivatives, the following evaluations were undertaken to determine their; (i) proteolytic resistances to pulmonary enzymes, (ii) bioactivities, and (iii) pulmonary pharmacokinetic and pharmacologic profiles. The results obtained showed that the pulmonary stabilities and pharmacokinetic properties of these derivatives were greatly improved by increasing PEG Mw. PEG-sCTs had 10.5-, 40.1-, and 1066.0-fold greater stabilities than that of sCT in rat lung homogenates. Moreover, all pharmacokinetic parameters (AUC(inf), C(max), t(1/2), and others) of these derivatives in endotracheally cannulated rats were significantly improved by PEGylation. Specifically, C(max) values increased on increasing PEG Mw, i.e., 78.1+/-21.1, 102.9+/-9.1, and 115.2+/-5.7 for 1, 2, 5 kDa, respectively, vs. 54.8+/-3.9 ng/mL for sCT. Their circulating t(1/2) values also increased to 53.9+/-6.0, 100.7+/-21.7, and 119.4+/-13.7 min, respectively, vs. 34.6+/-7.6 min for sCT. Despite having the best properties, Lys(18)-PEG(5k)-sCT was found to have significantly lower hypocalcemic efficacy than other PEG-sCTs, probably due to its reduced intrinsic bioactivity ( approximately 30% vs. sCT). Rather, Lys(18)-PEG(2k)-sCT showed the most promising pulmonary potential because of its well-preserved bioactivity (>80% of sCT). Taken together, our findings suggest that the site-specific substitution to peptides like sCT with a PEG of an appropriate size offers optimized therapeutic potential by dual advantages, i.e., (i) increased proteolytic stability and (ii) extended circulating half-life in terms of intrapulmonary delivery.
Yu Seok Youn; Min Jung Kwon; Dong Hee Na; Su Young Chae; Seulki Lee; Kang Choon Lee
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-10-22
Journal Detail:
Title:  Journal of controlled release : official journal of the Controlled Release Society     Volume:  125     ISSN:  1873-4995     ISO Abbreviation:  J Control Release     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2007-12-10     Completed Date:  2008-01-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8607908     Medline TA:  J Control Release     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  68-75     Citation Subset:  IM    
College of Pharmacy, Pusan National University, Jangjun-dong, Geumjeong-gu, Busan 609-735, Korea.
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MeSH Terms
Administration, Inhalation
Biological Availability
Bone Density Conservation Agents / administration & dosage*,  chemistry,  pharmacokinetics
Calcitonin / administration & dosage*,  chemistry,  pharmacokinetics
Calcium / blood
Cell Line, Tumor
Cyclic AMP / metabolism
Drug Carriers / chemistry*
Drug Stability
Lung / enzymology,  metabolism*
Molecular Structure
Molecular Weight
Polyethylene Glycols / chemistry*
Rats, Sprague-Dawley
Reg. No./Substance:
0/Bone Density Conservation Agents; 0/Drug Carriers; 0/Polyethylene Glycols; 47931-85-1/salmon calcitonin; 60-92-4/Cyclic AMP; 7440-70-2/Calcium; 9007-12-9/Calcitonin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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