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FIGURE 15.3 Carl Alving.
in the macrophages, thus greatly decreasing the drug's systemic toxicity. Alving encapsu-
lated the antimonial drugs meglumine antimoniate and sodium stibogluconate into lipo-
somes composed of phospholipids with disaturated chains (DPPC), cholesterol, and an
anionic lipid. When encapsulated into liposomes, both drugs were more than 700 times
more active than either of the free (unencapsulated) drugs when tested in hamsters [7] .
4. Development of Liposomes that Avoid the RES
The purpose of developing liposome-sequestered drugs is to increase the therapeutic index
of the drug while minimizing its side effects. For most potential applications of drug-seques-
tered liposomes, being largely removed by the RES in a first pass through the circulatory
system is a fatal flaw. Therefore countless attempts have been made to avoid the RES and
thus enhance liposome circulation time [8,9] . The simplest method is to first inject empty lipo-
somes (free of drug) to satiate the RES before the drug-encapsulated liposomes are injected.
Most attempts to make long-circulating liposomes have involved changing liposomal proper-
ties by altering their lipid composition, size, and charge. As a general rule, small liposomes
have longer circulation lifetimes than do larger liposomes [10] . Unfortunately, small unilamel-
lar vesicles (SUVs) have much smaller sequestered volumes than large unilamellar vesicles
(LUVs), (discussed in Chapter 13), and so have diminished drug-carrying capacities. Even
worse are the multi-lamellar vesicles (MLVs) that are both large and have a very limited
sequestered aqueous space. Most of an MLV's sequestered space is occupied by lipid bilayers.
In 1982 Senior and Gregoriadis [10] reported that saturated chain PCs and SM (both lipids
have high T m s, see Chapter 5) have longer circulating half-lives than unsaturated PCs. Choles-
terol, a phospholipid-'condensing' sterol, also increased liposome circulation time. On the
other hand, positively charged liposomes are useless as drug carrying agents since they are
toxic. A major advance in producing long-circulating liposomes came from studies on the
surface of erythrocytes that manage to avoid the RES for their entire life of ~127 days. These
liposomes had their surfaces modified with gangliosides (particularly GM1, discussed in
Chapters 5 and 7) and sialic acid derivatives [11] . Therefore, the modified liposomes had
surface properties similar to erythrocytes. GM-liposomes have additional advantages in being
useful to deliver drugs by oral administration and being able to cross the blood
brain barrier.
The explanation of GM1 in RES avoidance relates to its flexible chain that occupies the space
e
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