Hydrophilic Carotenoids: Carotenoid Aggregates - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 51

Sensitizer, 1 O 2

Light

HCl/MeOH reflux

Heat

FIGURE 3.14 Stability of carotenoid aggregates.

In pure water, electron or energy transfer to carotenoid aggregates is obstructed by the membrane
of outside-directed polar groups (Sliwka et al. 2007), Figure 3.14.
Water-soluble crocin, 3.7 , and the lysine derivative, 3.20 , are immediately reactive in aqueous
solutions, whereas water-dispersible carotenoids only become reactive when contacting a milieu
in which the aggregates are disrupted. Dispersions of carotenoid aggregates will therefore have
increased shelf lives compared to monomolecular carotenoid formulations. When water is removed
azeotropically or by freeze-drying from carotenoid aggregate suspensions, and the remainder is fur-
ther dried at high vacuum, the residue could not always be dissolved in the solvent used for prepar-
ing the monomeric solutions. Most likely, water-containing aggregates survive the drying process,
stabilize the hydrophobic membrane, and resist dissolution by organic solvents.

3.7 BIOPHYSICAL AND BIOLOGICAL ACTIVITY OF HYDROPHILIC
CAROTENOIDS AND CAROTENOID AGGREGATES
As has been pointed out earlier in this chapter, the dietary consumption and historical medicinal
use of carotenoids has been well documented. In the modern age, in addition to crocin, 3.7 , and
norbixin, 3.8 , several carotenoids have become extremely important commercially. These include,
in particular, astaxanthin, 3.6 (i sh, swine, and poultry feed, and recently human nutritional supple-
ments); lutein, 3.4 , and zeaxanthin, 3.3 (animal feed and poultry egg production, human nutritional
supplements); and lycopene, 3.2 (human nutritional supplements). The inherent lipophilicity of these
compounds has limited their potential applications as hydrophilic additives without signii cant for-
mulation efforts; in the diet, the lipid content of the meal increases the absorption of these nutrients,
however, parenteral administration to potentially effective therapeutic levels requires separate for-
mulation that is sometimes ineffective or toxic (Lockwood et al. 2003).
Signii cant work began in 2002 to produce rational chemical derivatives of carotenoids that
might be utilized in human medicinal applications, by a globally connected multidisciplinary group
of researchers. Retrometabolic drug design was used to produce derivatives with novel characteris-
tics to be exploited in such applications, hopefully without introducing chemical toxicity not inher-
ent in the starting scaffold astaxanthin, 3.6 . The prototypical astaxanthin derivatives were produced
at kg scale as disuccinate sodium salts (Frey et al. 2004); the trade name of the compound under
development was Cardax, 3.19 . Cardax, 3.19 , underwent thorough preclinical evaluation, both as
a water-dispersible radical scavenger (Cardounel et al. 2003), Table 3.3, as well as an in vivo oral
and parenteral myocardial salvage agent, Figure 3.15 (Gross and Lockwood 2004, 2005, Lauver
et al. 2005, Gross et al. 2006, Lockwood et al. 2006a).
The aggregation and surface properties of Cardax, 3.19 , in various aqueous formulations were
comprehensively evaluated in 2005 (Foss et al. 2005c), as well as the potential plasma protein bind-
ing in mammalian applications with molecular modeling (Zsila et al. 2003). Cardax, 3.19 , proved