Preparation and characterization of stable pH-sensitive vesicles composed of α-tocopherol hemisuccinate.
The current study aims to develop a stable pH-sensitive drug delivery system. First, cleavable polyethylene glycol-α-tocopherol hemisuccinate (PEG-THS) was synthesized. Conventional pH-sensitive vesicles composed of the Tris salt of α-tocopherol hemisuccinate (THST) were then prepared using the detergent removal technique. The vesicles had a mean particle size of (163.8 ± 5.5) nm and a zeta potential of -74.5 ± 6.4 mV. The THST vesicles were then modified using PEG-THS or uncleavable PEG-cholesterol (PEG-CHOL) (THST/PEG-lipids, 100:6 molar ratio). The mean vesicle particle size and absolute zeta potential decreased with increasing PEG-THS proportion. When the pH was decreased, the vesicle particle size and calcein release rate increased. The THST vesicles were initially Ca(2+)-unstable but exhibited significantly improved stability after modification with PEG-THS, especially at PEG-lipid ratios above 6%. Incubation in an acid serum increased the calcein release rate of conventional THST vesicles to 45 ± 1.98% at 10 min. However, the release rate of the PEG-CHOL vesicles remained low. The calcein release rate of PEG-THS vesicles was between those of conventional and PEG-CHOL-V. Therefore, PEG-THS can protect vesicles in serum and reconstitute their pH sensitivity in acidic conditions. Cleavable PEG-THS can be used in stable pH-sensitive preparations without loss of pH sensitivity. Free calcein and conventional vesicles eliminated from the plasma soon after injection, as well as the half-life (t(1/2)) and area under the curve of PEG-THS-V encapsulating calcein, were dramatically increased. This phenomenon indicates that the use of PEG-lipid derivatives has gained a favorably long circulation effect in mice.
College of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, People's Republic of China. huan.xu1@163.com
Huan
H
Xu
Yi-Hui
YH
Deng
Kai-Qian
KQ
Wang
Da-Wei
DW
Chen
D000818:Animals; D019540:Area Under Curve; D002021:Buffers; D002118:Calcium / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D005452:Fluoresceins / Q000737:chemistry; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D044967:Serum / Q000737:chemistry; D012996:Solutions / Q000737:chemistry; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics
D002021:Buffers; D005452:Fluoresceins; D008055:Lipids; D012996:Solutions; D011092:Polyethylene Glycols; D002784:Cholesterol; D024502:alpha-Tocopherol; D002118:Calcium; C007740:fluorexon