TY - JOUR
T1 - Improved intrapulmonary delivery of site-specific PEGylated salmon calcitonin
T2 - Optimization by PEG size selection
AU - Youn, Yu Seok
AU - Kwon, Min Jung
AU - Na, Dong Hee
AU - Chae, Su Young
AU - Lee, Seulki
AU - Lee, Kang Choon
PY - 2008/1/4
Y1 - 2008/1/4
N2 - 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 Lys18-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 (AUCinf, Cmax, t1/2, and others) of these derivatives in endotracheally cannulated rats were significantly improved by PEGylation. Specifically, Cmax 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 t1/2 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, Lys18-PEG5k-sCT was found to have significantly lower hypocalcemic efficacy than other PEG-sCTs, probably due to its reduced intrinsic bioactivity (∼ 30% vs. sCT). Rather, Lys18-PEG2k-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.
AB - 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 Lys18-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 (AUCinf, Cmax, t1/2, and others) of these derivatives in endotracheally cannulated rats were significantly improved by PEGylation. Specifically, Cmax 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 t1/2 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, Lys18-PEG5k-sCT was found to have significantly lower hypocalcemic efficacy than other PEG-sCTs, probably due to its reduced intrinsic bioactivity (∼ 30% vs. sCT). Rather, Lys18-PEG2k-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.
KW - Intrapulmonary delivery
KW - PEGylation
KW - Salmon calcitonin
UR - http://www.scopus.com/inward/record.url?scp=36649019135&partnerID=8YFLogxK
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U2 - 10.1016/j.jconrel.2007.10.008
DO - 10.1016/j.jconrel.2007.10.008
M3 - Article
C2 - 18023905
AN - SCOPUS:36649019135
VL - 125
SP - 68
EP - 75
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 1
ER -