pH-sensitive liposomes from test tube to animal model

Author

Dexi Liu

Date of Award

5-1990

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

Leaf Huang

Committee Members

John Koontz, Wesley D. Wicks, Bruce Babbitt, Barry T. Rouse

Abstract

The therapeutic potential of liposomes as drug-delivery vehicles depends on the efficient delivery of liposome-entrapped compounds to cells. A number of studies have demonstrated in culture cells that pHsensitive liposomes composed of dioleoylphosphatidylethanolamine and oleic acid (DOPE/OA) show a high efficiency of delivery. However, these liposomes have not been successfully used in animals due to the poor stability of liposomes in serum and the rapid uptake by the reticuloendothelial system (RES) once administered into animals. The studies described in this dissertation were intended to explore the mechanisms of instability of liposomes in serum and the RES uptake and to engineer a new type of liposome which is serum-stable, pH-sensitive and exhibits prolonged circulation in animals. The stability of liposomes in blood was studied in a simplified in vitro system, i.e., in human plasma at 37°C. It was demonstrated that the stability of liposomes composed of dioleoylphosphatidylethanolamine and oleic acid is size dependent. Small liposomes (d ≤ 200 nm) are stable in plasma. Large ones are not stable, but the stability of large liposomes in plasma can be increased by including cholesterol in the liposome membranes. More detailed experiments with purified serum proteins show that the small liposomes are actually stabilized by lipoproteins. Apo A1 in the high density lipoproteins (HDL) shows a very strong stabilization effect. The stabilized liposomes are no longer pH-sensitive because of the insertion of proteins and/or lipids into the bilayer of liposomes and removal of OA from liposomes by serum albumin. The biodistribution of DOPE/OA based liposomes shows that ganglioside GM₁, GT_1b as well as high phase transition temperature lipids such as distearoylphosphatidylcholine (DSPC), once incorporated into the DOPE/OA liposome membranes, can increase the circulation time in blood due to a significant decrease of RES uptake of the liposomes. The DOPE based liposomes containing a double chain pH sensor, dipalmitoylsuccinylglycerol (DPSG), which tends to be resistant to removal from liposomes and hence maintains the pH-sensitivity of the liposomes, and GM₁, which meant to increase the circulation time of liposomes, show a good compromise between pH-sensitivity (40-50% release of entrapped contents at pH 4.0) and a relatively prolonged residence time in the circulation. The stability of DOPE based liposomes in plasma is important when compared with that of PC based liposomes. It seems that the small liposomes composed of DOPE/OA interact with the serum proteins in different mechanisms from those of the PC based liposomes. The results suggest that PE based liposomes may have a better chance to serve as an efficient drug carrier than the PC based liposomes in vivo as far as the pH-sensitivity and high efficiency of delivery are concerned.

Recommended Citation

Liu, Dexi, "pH-sensitive liposomes from test tube to animal model. " PhD diss., University of Tennessee, 1990.
https://trace.tennessee.edu/utk_graddiss/11446