Page 42 - CW E-Magazine (Oct-Nov-2023)

Drug Formulation

transition temperature range of a lipid fect of cholesterol not only reduces the escape of genetic material into the cy-
mixture. Whether or not the cholesterol dynamics of the individual lipids in the toplasm, which improves the overall
will lower or increase the phase transi- vesicle, but also influences the thick- therapeutic efficacy. Cholesterol plays a
tion temperature of a specific lipid mix- ness, compressibility, water penetration vital role in most LBDDS by enhancing
ture depends on several variables: the and intrinsic curvature, increasing the the overall stability of the formulation
acyl chain length of the lipids, the de- membrane’s mechanical stiffness while and transfection efficacy .
5,6
gree of unsaturation of the acyl chains, maintaining its fluidity .
4
and the cholesterol concentration. Cho- Cholesterol-saponin affinity: unlock-
lesterol can broaden the phase tran- Overall, cholesterol can provide ing the potential of ISCOMs for
sition temperature of lipid mixtures, structural support and stability for enhanced vaccine efficacy
which is especially useful when using LBDDS. Cholesterol is primarily vital Cholesterol doesn’t elicit an im-
saturated lipids like distearoylphospha- for maintaining the integrity of lipid- mune response in itself; however, it’s
tidylcholine (DSPC) that have higher delivery systems. However, cholesterol used to stabilise certain liposomal adju-
phase transition temperatures. The use has also been shown to play a crucial vant systems and ISCOMs. Saponins –
of cholesterol results in a vesicle that role in the efficient intracellular deliv- such as Quil-A and QS-21 for example
is more likely to retain its cargo and ery of LNPs and improved gene trans- – have a strong affinity for cholesterol
is less “leaky”. Cholesterol is used in fection. One factor in cholesterol’s and this affinity creates an interesting
many lipid systems from liposomes to ability to enhance transfection efficien- situation: If used alone as adjuvants in
LNPs. cy is its ability to promote membrane a vaccine, they bind to the biological
fusion. Cholesterol-rich domains near cholesterol of the cell membranes cre-
Cholesterol is a major component the surface of an LNP can interact with ating pores and this results in undesired
of many LBDDS. Cholesterol inserts cholesterol-rich domains on cell mem- reactogenicity at the site of the injec-
itself between phospholipids in lipid branes. This can lead to the formation tion. However, the same cholesterol af-
formulations. Its polar hydroxyl group of lipid rafts and facilitate the fusion of finity of saponins enabled scientists to
aligns with the polar headgroup of the the lipid-delivery system with a target develop both the mentioned ISCOMs
phospholipid, and its highly non-polar cell. This, in turn, enhances the inter- and liposomal adjuvant systems such
part is deeply immersed in the phos- nalisation of the therapeutic payload as AS01.
pholipid vesicle. Cholesterol’s planar into the cell where it is released. The
steroid ring generates a conformation- cholesterol-rich domains not only assist ISCOMs are spherical open cage-
ally rigid structure, and when it is pres- the internalisation of the payload, but like adjuvant systems that are formed
ent in large amounts in the lipid vesicle, also the payload’s endosomal escape by adjuvant-active saponin, choles-
cholesterol introduces conformational once the lipid delivery system is inter- terol, phospholipid, and antigen. The
ordering of the lipid chains acting as a nalized. Cholesterol-rich domains have ISCOM matrix consists of the same
permeability barrier. This ordering ef- been shown to assist the endosomal composition, shape, and morphology
as the ISCOM complex, minus the in-
corporated antigen. Demonstrated in
animal models ISCOMs enhance the
antigen targeting, uptake and activity of
antigen presenting cells including den-
dritic cells, B cells and macrophages.
This results in the production of pro-
inflammatory cytokines, namely inter-
leukin IL-1, IL-6 and IL-12 in addition
to enhanced expression of costimula-
tory molecules major histocompatibil-
ity complex (MHC) class II, B7.1 and
B7.2 .
7
Deemed to be designed as the ul-
timate adjuvant formulation when it
comes to efficacy, ISCOMs expand the

38 Chemical Weekly October / November 2023