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A liposome is a small artificial
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug delivery vehicles for
administration Administration may refer to: Management of organizations * Management, the act of directing people towards accomplishing a goal ** Administrative assistant, Administrative Assistant, traditionally known as a Secretary, or also known as an admini ...
of
pharmaceutical drug A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
s and
nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s, such as
lipid nanoparticles lipid nanoparticles (LNPs), are nanoparticles composed of lipids. They are a novel pharmaceutical drug delivery system (and part of nanoparticle drug delivery), and a novel pharmaceutical formulation. LNPs as a drug delivery vehicle were f ...
in mRNA vaccines, and
DNA vaccines A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response. DNA vaccines work by injecting genetically engineered plasmid containing the D ...
. Liposomes can be prepared by disrupting biological membranes (such as by sonication). Liposomes are most often composed of
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
s, especially phosphatidylcholine and
cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
, but may also include other lipids, such as
egg An egg is an organic vessel grown by an animal to carry a possibly fertilized egg cell (a zygote) and to incubate from it an embryo within the egg until the embryo has become an animal fetus that can survive on its own, at which point the a ...
,
phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. ''S''-Adenosyl methionine can s ...
, as long as they are compatible with lipid bilayer structure. A liposome design may employ surface
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s for attaching to unhealthy tissue. The major types of liposomes are the multilamellar vesicle (MLV, with several
lamellar phase Lamellar phase refers generally to packing of polar-headed long chain nonpolar-tail molecules in an environment of bulk polar liquid, as sheets of bilayers separated by bulk liquid. In biophysics, polar lipids (mostly, phospholipids, and rarely, gly ...
lipid bilayers), the small unilamellar liposome vesicle (SUV, with one lipid bilayer), the large unilamellar vesicle (LUV), and the cochleate vesicle. A less desirable form are multivesicular liposomes in which one vesicle contains one or more smaller vesicles. Liposomes should not be confused with
lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
s, or with
micelle A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloidal suspension (also known as associated collo ...
s and reverse micelles composed of
monolayer A monolayer is a single, closely packed layer of atoms, molecules, or cells. In some cases it is referred to as a self-assembled monolayer. Monolayers of layered crystals like graphene and molybdenum disulfide are generally called 2D materials. ...
s.Stryer S. (1981) Biochemistry, 213


Discovery

The word ''liposome'' derives from two Greek words: ''lipo'' ("fat") and ''soma'' ("body"); it is so named because its composition is primarily of phospholipid. Liposomes were first described by British haematologist Alec Douglas Bangham in 1961 (published 1964), at the Babraham Institute, in Cambridge. They were discovered when Bangham and R. W. Horne were testing the institute's new
electron microscope An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
by adding negative stain to dry phospholipids. The resemblance to the plasmalemma was obvious, and the microscope pictures served as the first evidence for the cell membrane being a bilayer lipid structure. Their integrity as a closed, bilayer structure, that could release its contents after detergent treatment (structure-linked latency) was established by Bangham, Standish and
Weissmann Weißmann (Weissmann, Weiszmann, Waismann) is a German surname meaning "white man". Common variants in spelling are Weismann, Weissman, Weisman, Waismann, and Vaisman. Science * Charles Weissmann, biochemist * Irving Weissman, scientist * Augus ...
in the next year. Weissmann - during a Cambridge pub discussion with Bangham - first named the structures "liposomes" after the lysosome, which his laboratory had been studying: a simple organelle the structure-linked latency of which could be disrupted by detergents and streptolysins. Liposomes can be easily distinguished from micelles and hexagonal lipid phases by negative staining transmission electron microscopy. Alec Douglas Bangham with colleagues Jeff Watkins and Malcolm Standish wrote the 1965 paper that effectively launched the liposome “industry”. Around this time he was joined at Babraham by Gerald Weissmann, an American physician with an interest in lysosomes. Now an emeritus professor at New York University School of Medicine, Weissmann recalls the two of them sitting in a Cambridge pub and reflecting on the role of lipid sheets in separating the interior of the cell from the exterior milieu. This insight, they felt, was to cell function what the discovery of the double helix had been to genetics. Bangham had called his lipid structures “multilamellar smectic mesophases” or sometimes “Banghasomes”. It was Weissmann who proposed the more user-friendly term liposome.


Mechanism

A liposome has an aqueous solution core surrounded by a
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...
membrane, in the form of a lipid bilayer; hydrophilic solutes dissolved in the core cannot readily pass through the bilayer. Hydrophobic chemicals associate with the bilayer. A liposome can be hence loaded with hydrophobic and/or hydrophilic molecules. To deliver the molecules to a site of action, the lipid bilayer can fuse with other bilayers such as the cell membrane, thus delivering the liposome contents; this is a complex and non-spontaneous event, however, that does not apply to nutrients and drug delivery. By preparing liposomes in a solution of DNA or
drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...
(which would normally be unable to diffuse through the membrane) they can be (indiscriminately) delivered past the lipid bilayer. Liposomes are used as models for artificial cells. Liposomes can also be designed to deliver drugs in other ways. Liposomes that contain low (or high) pH can be constructed such that dissolved aqueous drugs will be charged in solution (i.e., the pH is outside the drug's pI range). As the pH naturally neutralizes within the liposome ( protons can pass through some membranes), the drug will also be neutralized, allowing it to freely pass through a membrane. These liposomes work to deliver drug by diffusion rather than by direct cell fusion. However, the efficacy of this pH regulated passage depends on the physiochemical nature of the drug in question (e.g. pKa and having a basic or acid nature), which is very low for many drugs. A similar approach can be exploited in the biodetoxification of drugs by injecting empty liposomes with a transmembrane pH gradient. In this case the vesicles act as sinks to scavenge the drug in the blood circulation and prevent its toxic effect. Another strategy for liposome drug delivery is to target
endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
events. Liposomes can be made in a particular size range that makes them viable targets for natural
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...
phagocytosis. These liposomes may be
digested Digestion is the breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorbed into the watery blood plasma. In certain organisms, these smaller substances are absorbed through the small inte ...
while in the macrophage's phagosome, thus releasing its drug. Liposomes can also be decorated with opsonins and
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s to activate endocytosis in other cell types. The use of liposomes for transformation or transfection of DNA into a host cell is known as lipofection. In addition to gene and drug delivery applications, liposomes can be used as carriers for the delivery of dyes to textiles, pesticides to plants, enzymes and nutritional supplements to foods, and cosmetics to the skin. Liposomes are also used as outer shells of some microbubble contrast agents used in contrast-enhanced ultrasound.


Dietary and nutritional supplements

Until recently, the clinical uses of liposomes were for targeted drug delivery, but new applications for the oral delivery of certain dietary and nutritional supplements are in development. This new application of liposomes is in part due to the low absorption and bioavailability rates of traditional oral dietary and nutritional tablets and capsules. The low oral bioavailability and absorption of many nutrients is clinically well documented. Therefore, the natural encapsulation of
lypophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipoph ...
and hydrophilic nutrients within liposomes would be an effective method of bypassing the destructive elements of the gastric system and
small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
s allowing the encapsulated nutrient to be efficiently delivered to the cells and tissues. The term
nutraceutical A nutraceutical or bioceutical is a pharmaceutical alternative which claims physiological benefits. In the US, "nutraceuticals" are largely unregulated, as they exist in the same category as dietary supplements and food additives by the FDA, unde ...
combines the words
nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
and pharmaceutical, originally coined by Stephen DeFelice, who defined nutraceuticals as “food or part of a food that provides medical or health benefits, including the prevention and/or treatment of a disease”. However, currently, there is no conclusive definition of nutraceuticals yet, to distinguish them from other food‐derived categories, such as food (dietary) supplements, herbal products, pre‐ and probiotics, functional foods, and fortified foods. Generally, this term is used to describe any product derived from food sources which is expected to provide health benefits additionally to the nutritional value of daily food. A wide range of nutrients or other substances with nutritional or physiological effects (EU Directive 2002/46/EC) might be present in these products, including vitamins, minerals, amino acids, essential fatty acids,
fibre Fiber or fibre (from la, fibra, links=no) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often incorporate ...
s and various plants and herbal extracts. Liposomal nutraceuticals contain bioactive compounds with health-promoting effects. The encapsulation of bioactive compounds in liposomes is attractive as liposomes have been shown to be able to overcome serious hurdles bioactives would otherwise encounter in the gastrointestinal (GI) tract upon oral intake. It is important to note that certain factors have far-reaching effects on the percentage of liposome that are yielded in manufacturing, as well as the actual amount of realized liposome entrapment and the actual quality and long-term stability of the liposomes themselves. They are the following: (1) The actual manufacturing method and preparation of the liposomes themselves; (2) The constitution, quality, and type of raw
phospholipid Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
used in the formulation and manufacturing of the liposomes; (3) The ability to create homogeneous liposome particle sizes that are stable and hold their encapsulated payload. These are the primary elements in developing effective liposome carriers for use in dietary and nutritional supplements.


Manufacturing

The choice of liposome preparation method depends, i.a., on the following parameters: # the physicochemical characteristics of the material to be entrapped and those of the liposomal ingredients; # the nature of the medium in which the lipid vesicles are dispersed # the effective concentration of the entrapped substance and its potential toxicity; # additional processes involved during application/delivery of the vesicles; # optimum size, polydispersity and shelf-life of the vesicles for the intended application; and, # batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products Useful liposomes rarely form spontaneously. They typically form after supplying enough energy to a dispersion of (phospho)lipids in a polar solvent, such as water, to break down multilamellar aggregates into oligo- or unilamellar bilayer vesicles. Liposomes can hence be created by sonicating a dispersion of amphipatic lipids, such as phospholipids, in water. Low shear rates create multilamellar liposomes. The original aggregates, which have many layers like an onion, thereby form progressively smaller and finally unilamellar liposomes (which are often unstable, owing to their small size and the sonication-created defects). Sonication is generally considered a "gross" method of preparation as it can damage the structure of the drug to be encapsulated. Newer methods such as extrusion, micromixing and Mozafari method are employed to produce materials for human use. Using lipids other than phosphatidylcholine can greatly facilitate liposome preparation.


Prospect

Further advances in liposome research have been able to allow liposomes to avoid detection by the body's immune system, specifically, the cells of reticuloendothelial system (RES). These liposomes are known as "
stealth liposome Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...
s". They were first proposed by G. Cevc and G. Blume and, independently and soon thereafter, the groups of L. Huang and V. Torchilin and are constructed with PEG ( Polyethylene Glycol) studding the outside of the membrane. The PEG coating, which is
inert Inert may refer to: * Chemically inert, not chemically reactive ** Inert gas ** Noble gas, historically called inert gas * Inert knowledge, information which one can express but not use * Inert waste, waste which is neither chemically nor biol ...
in the body, allows for longer circulatory life for the drug delivery mechanism. Studies have also shown that PEGylated liposomes elicit anti-IgM antibodies, thus leading to an enhanced blood clearance of the liposomes upon re-injection, depending on lipid dose and time interval between injections. In addition to a PEG coating, some stealth liposomes also have some sort of biological species attached as a ligand to the liposome, to enable binding via a specific expression on the targeted drug delivery site. These targeting ligands could be
monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...
(making an immunoliposome), vitamins, or specific antigens, but must be accessible. Targeted liposomes can target certain cell type in the body and deliver drugs that would otherwise be systemically delivered. Naturally toxic drugs can be much less systemically toxic if delivered only to diseased tissues. Polymersomes, morphologically related to liposomes, can also be used this way. Also morphologically related to liposomes are highly deformable vesicles, designed for non-invasive transdermal material delivery, known as transfersomes. Certain anticancer drugs such as doxorubicin (Doxil) and daunorubicin may be administered via liposomes. Liposomal cisplatin has received
orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...
designation for pancreatic cancer from EMEA. Liposomes can be used on their own or in combination with traditional antibiotics as neutralizing agents of bacterial toxins. Many bacterial toxins evolved to target specific lipids of the host cells membrane and can be baited and neutralized by liposomes containing those specific lipid targets. A study published in May 2018 also explored the potential use of liposomes as "nano-carriers" of fertilizing nutrients to treat malnourished or sickly plants. Results showed that these synthetic particles "soak into plant leaves more easily than naked nutrients", further validating the utilization of nanotechnology to increase crop yields.


See also

* Azotosome * Lamella (cell biology) *
Langmuir–Blodgett film A Langmuir–Blodgett (LB) film is a nanostructured system formed when Langmuir films—or Langmuir monolayers (LM)—are transferred from the liquid-gas interface to solid supports during the vertical passage of the support through the monolayers ...
* Lipid bilayer * Targeted drug delivery


References


External links


Journal of Liposome Research
{{Dosage forms, state=expanded Membrane biology Drug delivery devices Dosage forms