Stereocontrolled total syntheses of plasmalogen and diplasmalogen lipids and their activities in an intracellular drug delivery system
Abstract
The objective of present study was to develop an efficient chemical synthesis method for the plasmalogen and diplasmalogen lipids and to investigate their potential applications in pH-sensitive liposomal drug delivery systems. A stereo-controlled preparation of cis-vinyl ether linkage was developed using an ester as precursor. At -78$\sp\circ$C, the ester was treated with LDA to generate enolate, which was then trapped with chlorodiethylphosphate, followed by the reduction of the vinyl phosphate with Et$\sb3$Al/Pd(PPh$\sb3)\sb4$ in hexane gave specifically cis-vinyl ether linkage. Plasmalogen was synthesized efficiently from 1-acyl-sn-glycerol using this vinyl ether chemistry developed; the synthesis of diplasmalogen was carried out starting from the 1,2-acyl-sn-glycerol and also improved for multi-gram-scale preparation. The cis-vinyl ether linkages in this class of lipids are extremely pH sensitive and easily hydrolyzed, causing lipid decomposition to generate fatty acid, aldehyde and corresponding alcohol. When exposed to the low pH, the liposomes that are comprised of this class of lipids release their contents rapidly because the lipid degradation causes defects on the liposome membrane. Calcein release studies demonstrated that the diplasmalogen liposome has unique plasma stability as well as high release efficiency triggered by acidic pH's and is $\sim$10 times faster than the plasmalogen liposome. Coupled with folate targeting mechanism, this diplasmalogen liposome released 83% of the encapsulated propidium iodide into the cytoplasm of KB cells within 8 hours of incubation. The cytotoxicity IC$\sb{50}$ of AraC encapsulated in diplasmalogen liposome was 0.49 $\mu$M, a $\sim$6,000-fold enhancement compared with direct drug application. A novel lipid, 1,2-di-O-hexadecyl-sn-glycero-3-(1$\sp\prime$-(2$\sp\prime\sp\prime $-R-hydroxy-3$\sp\prime\sp\prime $-N-(5-amino-1-carboxypentyl))-iminodiacetic acid) (DHGN), was also synthesized for the monolayer-interfacial protein crystallization studies.
Degree
Ph.D.
Advisors
Thompson, Purdue University.
Subject Area
Organic chemistry|Pharmacology|Oncology
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