Effect of glycolipids on phospholipid interaction and liposome circulation

Author

Yong Serk Park

Date of Award

5-1992

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

Leaf Huang

Committee Members

Jorge E. Churchich, Engin Sepersu, Jeffery Becker

Abstract

A series of glycophospholipids has been synthesized by coupling mono-, di-, or trisaccharides to dioleoylphos-phatidylethanolamine (DOPE) via reductive amination to study effect of glycosyl headgroup on lipid polymorphism. The ability of glycophospholipid to stabilize the DOPE bilayer phase was directly related to the hydration intensity. Glycophospholipids generally reduced the chain-melting temperature (T_m) of dipalmitoylphosphatidylcholine (DPPC). Low level of N-(Nacetylneuraminlactosyl- DOPE (NANL-DOPE) reduced the membrane fluidity of DPPC as well as increased the hexagonal phase transition temperature (T_H) of dioleoylphosphatidylethanolamine (DEPE); whereas the other glycophospholipids did not. Trisaccharide-DOPE, i.e. Nisomaltosyl DOPE and NANL-DOPE had similar activity in cryoprotection, whereas mono- and disaccharide-DOPE, i.e. N-galactosy-DOPE and Nlactosyl- DOPE, did not show any activity, and even reduced the cryoprotective effect of trehalose, a well-known cryoprotectant.

To investigate the effect of glycosyl beadgroup on liposome biodistribution, several derivatives of phospholipid or glycolipid were synthesized: (1) a series of negatively charged phospholipid derivatives, (2) ganglioside G_m1 derivatives in which the sugar group had been modified by periodate oxidation, reduction, or reductive amination, (3) G_m1 derivatives in which the negative charge of sialic acid has been removed by methylation or reductive hydrolysis, (4) neoglycolipid analogs of G_m1 synthesized by coupling the G_m1 oligosaccharide to DOPE via different spacer arms. The derivatives were incorporated into egg PC/ cholesterol liposomes to test their effects on prolonging the liposome circulation. Only N-glutaryl DOPE and N-adipyl DOPE were effective in prolonging the liposome circulation. The oxidized G_m1 was ineffective in prolonging the liposome circulation and however, the lost activity was completely recovered by subsequent reduction or some reductive amination. Removal of the negative charge of G_m1 did not deprive of its activity. Among the neo glycolipid analogs of G_m1, only G_m1 oligosaccharide directly conjugated to DOPE was effective in prolonging the circulation. Lipid A was included in the liposomes containing G_m1 or poly(ethyleneglycol)-PE (PEG-PE) and its effect on the liposome biodistribution was also investigated. Lipid A, being an opsonizing lipid, more effectively antagonized G_m1 activity than PEG-PE's in prolonging the liposome circulation. This may be related to the different mechanisms exerted by G_m1 and PEG-PE. These results indicate that the molecular structures of the negatively charged DOPE derivative and Gm oligosaccharide are very important for their functional activities in prolonging the liposome circulation,which may be regulated by putative "dysopsonin(s) ".

Recommended Citation

Park, Yong Serk, "Effect of glycolipids on phospholipid interaction and liposome circulation. " PhD diss., University of Tennessee, 1992.
https://trace.tennessee.edu/utk_graddiss/10973