TY - JOUR
T1 - PEGylation of the GALA Peptide Enhances the Lung-Targeting Activity of Nanocarriers That Contain Encapsulated siRNA
AU - Santiwarangkool, Sarochin
AU - Akita, Hidekata
AU - Nakatani, Taichi
AU - Kusumoto, Kenji
AU - Kimura, Hiroki
AU - Suzuki, Masaru
AU - Nishimura, Masaharu
AU - Sato, Yusuke
AU - Harashima, Hideyoshi
N1 - Publisher Copyright:
© 2017 American Pharmacists Association®
PY - 2017/9
Y1 - 2017/9
N2 - A α-helical GALA peptide (WEAALAEALAEALAEHLAEALAEALEALAA) has been found to possess dual functions: a pH-dependent inducer of endosomal escape, and a ligand that targets lung endothelium. In the present study, the flexibility of GALA was improved by modifying the edge with polyethylene glycol linker, to increase lung-targeting activity. We first investigated the uptake of the GALA-modified liposomes in which GALA was directly conjugated to the lipid (Cholesterol: GALA/Chol) or the phospholipid-PEG (GALA/PEG2000). The liposomes that were modified with GALA/PEG2000 (GALA/PEG2000-LPs) were taken up at a higher level by human lung endothelial cells (HMVEC-L), in comparison with particles that were modified with GALA/Chol (GALA/Chol-LPs). Small-interfering RNA–encapsulating liposomal-based nanocarriers (multifunctional envelope-type nano device: MEND) that were formulated with a vitamin E-scaffold SS-cleavable pH-activated lipid-like material, namely GALA/PEG2000-MENDssPalmE were also modified with GALA/PEG2000. Gene silencing activity in the lung endothelium was then evaluated against an endothelial marker; CD31. In comparison with the unmodified MENDssPalmE, GALA/PEG2000-MENDssPalmE exhibited a higher silencing activity in the lung. Optimization of GALA/PEG2000-MENDssPalmE resulted in silencing activity in the lung with an ED50 value of 0.21 mg/kg, while non-specific gene silencing in liver was marginal. Collectively, PEGylated GALA is a promising device for use in targeting the lung endothelium.
AB - A α-helical GALA peptide (WEAALAEALAEALAEHLAEALAEALEALAA) has been found to possess dual functions: a pH-dependent inducer of endosomal escape, and a ligand that targets lung endothelium. In the present study, the flexibility of GALA was improved by modifying the edge with polyethylene glycol linker, to increase lung-targeting activity. We first investigated the uptake of the GALA-modified liposomes in which GALA was directly conjugated to the lipid (Cholesterol: GALA/Chol) or the phospholipid-PEG (GALA/PEG2000). The liposomes that were modified with GALA/PEG2000 (GALA/PEG2000-LPs) were taken up at a higher level by human lung endothelial cells (HMVEC-L), in comparison with particles that were modified with GALA/Chol (GALA/Chol-LPs). Small-interfering RNA–encapsulating liposomal-based nanocarriers (multifunctional envelope-type nano device: MEND) that were formulated with a vitamin E-scaffold SS-cleavable pH-activated lipid-like material, namely GALA/PEG2000-MENDssPalmE were also modified with GALA/PEG2000. Gene silencing activity in the lung endothelium was then evaluated against an endothelial marker; CD31. In comparison with the unmodified MENDssPalmE, GALA/PEG2000-MENDssPalmE exhibited a higher silencing activity in the lung. Optimization of GALA/PEG2000-MENDssPalmE resulted in silencing activity in the lung with an ED50 value of 0.21 mg/kg, while non-specific gene silencing in liver was marginal. Collectively, PEGylated GALA is a promising device for use in targeting the lung endothelium.
KW - DNA/oligonucleotide delivery
KW - PEGylation
KW - biomaterials
KW - endothelial
KW - gene delivery
KW - nanoparticles
KW - nanotechnology
KW - siRNA
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UR - http://www.scopus.com/inward/citedby.url?scp=85023610918&partnerID=8YFLogxK
U2 - 10.1016/j.xphs.2017.04.075
DO - 10.1016/j.xphs.2017.04.075
M3 - Article
C2 - 28483420
AN - SCOPUS:85023610918
SN - 0022-3549
VL - 106
SP - 2420
EP - 2427
JO - Journal of pharmaceutical sciences
JF - Journal of pharmaceutical sciences
IS - 9
ER -