Lipid conjugates

In lower organisms the structural analysis was reported of a new glyco-sphingolipid (GSL) from the LPS-lacking Sphingomonas adhaesiva (whilst in 

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Recknagel, R.O. and Glende, E.A. (1984). Spectrophotometric detection of lipid conjugated dienes. Methods in Enzymology 105 331-337. 

Teramura Y, Ln M, Kawamoto T et al (2010) Microencapsulation of islets with living cells using polyDNA-PEG-lipid conjugate. Bioconjug Chem 21 792-796... 

On the other hand, in rats, a single dose of 6,156 mg/kg hexachloroethane in mineral oil had no effects on a different set of biochemical indicators of liver function (microsomal protein, oxidative demethylase, NADP-NT reductase, glucose-6-phosphatase, or lipid conjugated diene concentration) when measured 2 hours after compound administration (Reynolds 1972). Each of these parameters is an indicator of microsomal function. The authors postulated that the observed lack of effects could have been the result of slow uptake of hexachloroethane by the liver in a 2-hour period. Gastrointestinal absorption of hexachloroethane in mineral oil is probably minimal because, unlike olive oil, mineral oil cannot be digested. Dissolved lipophilic materials could be excreted in the feces soon after administration because mineral oil can act as a laxative. Thus, the author s hypothesis that minimal hexachloroethane would reach the liver in 2 hours is reasonable. 

Another feature of diacids of interest in prodrug design is that the free carboxy group of a drug R-COOH can be used to attach an additional carrier group R OH, e.g., R-CO-Cf -Cf -CO-OR. An example of this type has been reported for a lipid conjugate of testosterone, with R = 2-(l,3-dipalmi-toyljglyccryl [133] (see also Sect. 8.2.5). 

A further group of AT-[(acyloxy)methyl] pro-moieties contains acidic and/or lipid-like substituents. Here again, most published results concern phenytoin. Thus, some phenytoin-lipid conjugates such as 8.183 and 8.186 (with R = various fatty acyl moieties) were reported [233]. Such prodrugs are, of course, insoluble in water but formed dispersions when briefly sonicated in EtOH/water mixtures containing sodium taurodeoxycholate. No significant hydrolysis was seen in buffer or plasma. In contrast, incubation with pancreatic lipase yielded the bis-deacyl derivatives (i.e., 8.182 and 8.185, respectively), with subsequent liberation of phenytoin the time for 50% liberation of phenytoin varied from 20 to 200 min under the conditions of the studies [233][234], The intermediates 8.182, 8.184, and 8.185 were also substrates for human and rat plasma hydrolases. 

After intraperitoneal administration, the phenytoin-lipid conjugates were at best equipotent with phenytoin in protection mice against seizures... 

D. M. Lambert, G. K. E. Scriba, J. H. Poupaert, P. Dumont, Anticonvulsant Activity of Ester- and Amide-Type Lipid Conjugates of Glycine and V-Benzyloxycarbonyl Glycine , Eur. J. Pharm. Sci. 1996, 4, 159-166. 

G. K. E. Scriba, Synthesis and in vitro Degradation of Testosterone-Lipid Conjugates , Arch. Pharm. 1995, 328, 271 -276. 

G. K. E. Scriba, Phenytoin-Lipid Conjugates Chemical, Plasma Esterase-Mediated, and Pancreatic Lipase-Mediated Hydrolysis in vitro, Pharm. Res. 1993, 10, 1181 — 1186. 

Riche EL, Erickson BW, Cho MJ. Novel long-circulating liposomes containing peptide library-lipid conjugates synthesis and in vivo behavior. J Drug Target 2004 12 355. 

Holland JW, Hui C, Cullis PR, Madden TD. Poly(ethylene glycol)-lipid conjugates regulate the calcium-induced fusion of liposomes composed of phos-phatidylethanolamine and phosphatidylserine. Biochemistry 1996 35 2618. 

Song L, et al. Characterization of the inhibitory effect of PEG-lipid conjugates on the intracellular delivery of plasmid and antisense DNA mediated by cationic lipid liposomes. Biochim Biophys Acta 2002 1558 1. 

Holland JW, Cullis PR, Madden TD. Poly(ethyleneglycol)-lipid conjugates promote bilayer formation in mixtures of non-bilayer-forming lipids. Biochemistry... 

Guo X, Szoka E. Steric stabilization of Fusogenic Liposomes by a low-pH sensitive PEG-diortho ester-lipid conjugate. Bioconj Chem 2001 12 291. 

Rejman J, et al. Characterization and transfection properties of lipoplexes stabilized with novel exchangeable polyethylene glycol-lipid conjugates. Biochim Biophys Acta 2004 1660 41. 

Trubetskoy, V. S. andV. P Torchilin. 1995. Use of polyoxyethylene-lipid conjugates as long-circulating carriers for delivery of therapeutic and diagnostic ageritdv. Drug Del. Rev16 311-320. 

Physicochemical Properties and Hydrolysis Rates for Phenytoin-Lipid Conjugates... 

Scriba, G K. E. 1993. Phenytoin-lipid conjugates chemical, plasma esterase-mediated, and pancreatic lipase-mediated hydrolysis vitro. Pharm. Res10 1181-1186. 

Lipid moieties coupled to polyethylene glycol (PEG) have been used to increase the blood circulation time of lipoplexes (Fig. 32). The PEG-lipid conjugates such as DOPE-PEG, Chol-PEG, ceramides-PEG and their derivatives are then coformulated with the cationic lipid, helper lipid, and DNA. This results in coating the surface of the lipoplexes with PEG and preventing undesired association with plasma proteins or circulating cells (stealth liposomes). Recently, a-tocopheryl PEG-succinate (TPGS) was also used in gene delivery formulations because of its ability to confer not only a stealth property but also antioxidant and absorption enhancer properties [129]. 

Guo, X., and Szoka, F. C., Jr. Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG-diortho ester—lipid conjugate. Bioconjug. Chem. 12(2) 291—300. 2001. 

To make scVEGF-lipid conjugate, add mPEG-DSPE-maleimide directly to deprotection reaction to a final molar protein-to-lipidratio of 1 2. Residual DTT will not affect modification reaction. Incubate lipidation reaction mixture at room temperature for 1 h. 

Insertion of scVEGF-Lipid Conjugate into Preformed Liposomes... 

In our experience, as little as 2-A h of incubation might be enough for insertion of 85-95% of lipid conjugate into liposome. Prolonged incubation (more than 16 h) does not improve the insertion in fact, it might result in a decreased amount of liposome-associated protein. 

Fig. (10). Agar diffusion of different proteins and a lipid conjugated with lactose against anti-lactose antibodies (well L) and against anti-BSA antibodies (Well BS) wells 1-6 contained Lac-poly, Lac-BSA, Lac-sphingosine, Lac-ORA, Lac-HGG and BSA Chemical modification of the antigen by periodate oxidation or borohydride reduction can effect an agar diffusion against anti-gum arabic antibodies (Se), GA=gum arabic Bl=blank.

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