Biology Reference
In-Depth Information
could be useful in targeting drugs to acidic tissues including tumors and sites of inflamma-
tion or infection.
For the last 20
years the most successful pH-sensitive liposomes have incorporated
succinate. The first use of this type of pH-sensitive liposome was reported by Leventis
et al. (1987)
[28]
. This group used a series of double chain amphiphiles, including 1,
2-dioleoyl-3-succinylglycerol (DOSG) that, when combined with POPE (16:0, 18:1 PE)
at pH 7.4 formed non-leaky liposomes. Importantly, these liposomes were fusogenic and
became leaky under mildly acidic conditions, but were stable in serum. A few years later,
Collins et al. (1990)
[29]
made a series of pH-sensitive liposomes from three similar diacyl-
succinylglycerols (including DOSG) and PE. These workers advanced the earlier report
[28]
by attaching an anti-H2k
k
antibody isolated from the murine hybridoma cell line 11-4.1
to the N-hydroxysuccinimide ester of palmitic acid, thus converting the pH-sensitive
liposome into a pH-sensitive 'immunoliposome'. Later additions attached a phosphate to
the glycerol sn-3 position (
Figure 15.6
, Panel B). Finally, the phosphate was replaced by a
PE (N-succinyl-1,2-dioleoylphosphatidylethanolamine) and PEG was attached to the PE.
Therefore the final product was a pH-sensitive, stealth, immunoliposome with tremendous
cytotoxic potential. This example emphasizes the versatility of liposomes for drug
targeting.
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B. EFFECT OF DIETARY LIPIDS ON MEMBRANE
STRUCTURE/FUNCTION
The old adage 'you are what you eat' certainly applies to the effect of dietary lipids on
membrane structure and function. At the vanguard of dietary fatty acids are both 'bad
guys,' trans fatty acids (TFAs) and 'good guys,' docosahexaenoic acid (DHA). Although
many other lipids also affect membranes, this chapter will only contrast TFA and DHA,
the alpha and omega of the fatty acid business, because of their topical interest in human
health.
1.
Fatty Acids
Dietary trans fatty acids (TFAs) terrify the health-conscious public, and for good reason.
Since the 1950s, TFAs have been closely linked to coronary heart disease and arteriosclerosis
[30]
. A 2004 report of the Harvard School of Public Health estimated that partially hydroge-
nated fat, the major dietary source of TFAs, may be responsible for between 30,000 and
100,000 premature coronary deaths per year in the United States alone
[31]
. To date, there
have been numerous large epidemiology studies that have strongly supported this conclu-
sion
[32]
. Much less certain are reports that TFAs may also be weakly carcinogenic
[33]
and may even affect normal brain function
[34]
. TFAs are now universally recognized to
be 'bad guys', but why? TFAs are very similar to cis fatty acids that are far more common
and are essential for life. So why have TFAs turned to the dark side?
For millennia, TFAs have been a normal component of human membranes. For example,
the sphingosine backbone of sphingolipids contains a trans double bond in its fixed hydro-
phobic chain. The simplest TFA, elaidic acid (18:1
D
9t
), is naturally present in ruminant fat,
Trans
