Page 187 - CW E-Magazine (17-10-2023)

Special Report Special Report

Cholesterol: enhancing stability and effi cacy in fect of cholesterol not only reduces the escape of genetic material into the as the ISCOM complex, minus the in-
dynamics of the individual lipids in the cytoplasm, which improves the overall corporated antigen. Demonstrated in
lipid-based drug delivery vesicle, but also infl uences the thick- therapeutic effi cacy. Cholesterol plays animal models ISCOMs enhance the
ness, compressibility, water penetration a vital role in most LBDDS by enhanc-
antigen targeting, uptake and activity of
ipid-based drug delivery sys- LBDDS can be tailored to meet also reduces permeability of the mem- and intrinsic curvature, increasing the ing the overall stability of the formula- antigen presenting cells including den-
tems (LBDDS) have gained requirements set by disease indication, brane(3). Since natural sterols play such membrane’s mechanical stiffness while tion and transfection effi cacy(5,6). dritic cells, B cells and macrophages.
Lsignifi cant attention in pharma- administration route, cost, active pharma- a crucial role in stabilising biological maintaining its fl uidity(4). This results in the production of pro-
ceutical research due to their versati- ceutical ingredient (API) stability, membranes, it’s not surprising that they Cholesterol-saponin affi nity: unlock- infl ammatory cytokines, namely inter-
lity and numerous benefi ts. LBDDS can toxicity and effi cacy(1). play a similarly important role in syn- Overall, cholesterol can provide ing the potential of ISCOMs for leukin IL-1, IL-6 and IL-12 in addition
overcome formulation challenges of thetic systems as well. Just as it stabilises structural support and stability for enhanced vaccine effi cacy to enhanced expression of costimula-
poorly water-soluble drugs by improv- LBDDS can be broadly grouped biological membranes, the presence LBDDS. Cholesterol is primarily vital Cholesterol doesn’t elicit an im- tory molecules major histocompatibi-
ing their solubility and bioavailability into solid lipid particulate dosage of cholesterol also fi lls gaps between for maintaining the integrity of lipid- mune response in itself; however, it’s lity complex (MHC) class II, B7.1 and
while offering controlled and targeted forms, emulsion-based systems, solid phospholipids to stabilise synthetic delivery systems. However, cholesterol used to stabilise certain liposomal adju- B7.2(7).
drug release, high drug content load- lipid tablets and vesicular systems. vesicle membranes. has also been shown to play a crucial vant systems and ISCOMs. Saponins –
ing, and stability. They can be used for role in the effi cient intracellular deli- such as Quil-A and QS-21 for example – Deemed to be designed as the ulti-
various administration routes and can Modifi cations to these groups Cholesterol is also effective at very of LNPs and improved gene trans- have a strong affi nity for cholesterol mate adjuvant formulation when it
be tailored to meet specifi c require- include, but are not limited to lipo- broadening the liquid crystalline phase fection. One factor in cholesterol’s and this affi nity creates an interesting comes to effi cacy, ISCOMs expand the
ments. Cholesterol, a key component spheres, lipid nanoparticles (LNPs), transition temperature range of a lipid ability to enhance transfection effi ciency situation: If used alone as adjuvants in immune response. Currently most ad-
in LBDDS, provides structural support liposomes, and self-emulsifying formu- mixture. Whether or not the cholesterol is its ability to promote membrane a vaccine, they bind to the biological juvants only activate the humoral im-
and stability, enhances the effi ciency of lations (SEFs)(2). will lower or increase the phase transi- fusion. Cholesterol-rich domains near cholesterol of the cell membranes cre- mune response; whereas ISCOMs are
intracellular delivery and gene trans- tion temperature of a specifi c lipid mix- the surface of an LNP can interact with ating pores and this results in undesired able to induce strong activation of both
fection, and plays a crucial role in the Lipids form self-assembled nano- ture depends on several variables: the cholesterol-rich domains on cell mem- reactogenicity at the site of the injec- the cell mediated and humoral arms of
formulation of immune stimulating structures such as liposomes or LNPs acyl chain length of the lipids, the de- branes. This can lead to the formation tion. However, the same cholesterol the immune system, generating long-
complexes (ISCOMs) and liposomal to deliver small molecules and nucleic gree of unsaturation of the acyl chains, of lipid rafts and facilitate the fusion of affi nity of saponins enabled scientists lasting biologically active antibodies
adjuvant systems. Additionally, plant- acids. Phospholipids are water-insolu- and the cholesterol concentration. Cho- the lipid-delivery system with a target to develop both the mentioned ISCOMs and a strong cellular response(8,9). In
based cholesterol offers a few benefi ts ble and form a phospholipid bilayer lesterol can broaden the phase tran- cell. This, in turn, enhances the inter- and liposomal adjuvant systems such addition to the immunological benefi ts,
as an alternative to egg- or animal- when mixed with water due to their sition temperature of lipid mixtures, nalisation of the therapeutic payload as AS01. ISCOMs technology can provide com-
based cholesterol for pharmaceutical amphipathic properties; however, the which is especially useful when using into the cell where it is released. The mercial benefi ts including great fl exi-
applications. lipid bilayers they form are unstable saturated lipids like distearoylphospha- cholesterol-rich domains not only assist ISCOMs are spherical open cage- bility in vaccine design due to the abi-
and prone to fall apart. This instabi- tidylcholine (DSPC) that have higher the internalisation of the payload, but like adjuvant systems that are formed lity to mix the ISCOMs matrix with the
The versatility and benefi ts of lipid- lity can be addressed by cholesterol, phase transition temperatures. The use also the payload’s endosomal escape by adjuvant-active saponin, choles- required antigen at the post-manufac-
based drug delivery a lipid component that can be used to of cholesterol results in a vesicle that once the lipid delivery system is inter- terol, phospholipid, and antigen. The turing stage. One of the most successful
Throughout the past decade pharma- provide structural support and stabilise is more likely to retain its cargo and nalized. Cholesterol-rich domains have ISCOM matrix consists of the same ISCOMs is the AS01b formulation used
ceutical research has focused on deve- nanoparticles. is less “leaky”. Cholesterol is used in been shown to assist the endosomal composition, shape, and morphology in the Zoster vaccine (Shingrix) which
lopment of novel drug delivery sys- many lipid systems from liposomes to has been proven to be effective at pre-
tems such as LBDDS, improving the Enhancing stability and functionality LNPs. venting Shingles in adults. This system
bioavailability of existing drugs while in synthetic and natural membranes is formulated with a combination of
reducing their toxicity. LBDDS can From a chemical point of view, Cholesterol is a major component monophosphoryl lipid A (MPLA) and
address common formulation challenges cholesterol is an amphipathic lipid be- of many LBDDS. Cholesterol inserts QS-21 adjuvants, as well as cholesterol
of poorly water-soluble drugs, e.g., longing to the class of sterols and con- itself between phospholipids in lipid and a phospholipid. AS01b is also being
solubility and bioavailability, while sisting of four hydrophobic rings and a formulations. Its polar hydroxyl group tested in clinical trials as a component
providing a range of benefi ts including hydrophilic hydroxyl moiety. Choles- aligns with the polar headgroup of the of Mosquirix (the fi rst approved mala-
controlled and targeted drug release, terol occurs naturally in both plants phospholipid, and its highly non-polar ria vaccine) and HIV vaccines. Choles-
high drug content loading (compared and animals – for example in animals part is deeply immersed in the phos- terol is an important component in
to other carriers), pharmaceutical sta- it is a precursor for the biosynthesis of pholipid vesicle. Cholesterol’s planar many ISCOMs, including AS01b, and
bility and excipient versatility. Lipid steroid hormones, bile acid and vita- steroid ring generates a conformation- is being investigated in next-generation
formulations can be used to formulate min D. It’s also an essential structural ally rigid structure, and when it is pre- AS01b-like systems.
pharmaceuticals across a range of dos- component of animal cell membranes sent in large amounts in the lipid vesicle,
age routes including oral, parenteral, composing about 30% of them. In addi- cholesterol introduces conformational Plant-based cholesterol
ocular, dermal, transdermal, and vagi- tion to providing strength and stability ordering of the lipid chains acting as a Currently, most cholesterol used in
nal. Further illustrating their versatility, in animal cell membranes, cholesterol permeability barrier. This ordering ef- industry is sourced from animal mate-

186 Chemical Weekly October 17, 2023 Chemical Weekly October 17, 2023 187

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