Aliposome is a small artificialvesicle, spherical in shape, having at least onelipid bilayer.[2] Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties,[2] liposomes can be used asdrug delivery vehicles foradministration ofpharmaceutical drugs andnutrients,[3] such aslipid nanoparticles inmRNA vaccines, andDNA vaccines. Liposomes can be prepared by disrupting biological membranes (such as bysonication).
Liposomes are most often composed ofphospholipids,[4] especiallyphosphatidylcholine, andcholesterol,[2] but may also include other lipids, such as those found inegg andphosphatidylethanolamine, as long as they are compatible withlipid bilayer structure.[5] A liposome design may employ surfaceligands for attaching to desired cells or tissues.[1]
Based on vesicle structure, there are seven main categories for liposomes: multilamellar large (MLV), oligolamellar (OLV), small unilamellar (SUV), medium-sized unilamellar (MUV), large unilamellar (LUV), giant unilamellar (GUV) and multivesicular vesicles (MVV).[6] The major types of liposomes are the multilamellar vesicle (MLV, with severallamellar phaselipid bilayers), the smallunilamellar liposome vesicle (SUV, with onelipid bilayer), the large unilamellar vesicle (LUV), and the cochleate vesicle. A less desirable form is multivesicular liposomes in which one vesicle contains one or more smaller vesicles.
Liposomes should not be confused withlysosomes, or withmicelles andreverse micelles.[8] In contrast to liposomes, micelles typically contain a monolayer of fatty acids or surfactants.[9]
The wordliposome derives from two Greek words:lipo ("fat") andsoma ("body"); it is so named because its composition is primarily of phospholipid.[citation needed]
Liposomes were first described by British hematologistAlec Douglas Bangham[10][11][12] in 1961 at the Babraham Institute, in Cambridge—findings that were published 1964. The discovery came about when Bangham and R. W. Horne were testing the institute's newelectron microscope by addingnegative stain to dry phospholipids. The resemblance to theplasmalemma was obvious, and the microscopic pictures provided the first evidence that the cell membrane is a bilayer lipid structure. The following year, Bangham, his colleague Malcolm Standish, andGerald Weissmann, an American physician, established the integrity of this closed, bilayer structure and its ability to release its contents following detergent treatment (structure-linked latency).[13] During a Cambridge pub discussion with Bangham, Weissmann first named the structures "liposomes" after something which laboratory had been studying, the lysosome: a simple organelle whose structure-linked latency could be disrupted by detergents and streptolysins.[14] Liposomes are readily distinguishable from micelles and hexagonal lipid phases through negative staining transmission electron microscopy.[15]
Bangham, with colleagues Jeff Watkins and Standish, wrote the 1965 paper that effectively launched what would become the liposome "industry." Around that same time, Weissmann joined Bangham at the Babraham. Later, Weissmann, then an emeritus professor at New York University School of Medicine, recalled the two of them sitting in a Cambridge pub, reflecting on the role of lipid sheets in separating the cell interior from its exterior milieu. This insight, they felt, would be to cell function what the discovery of the double helix had been to genetics. As Bangham had been calling his lipid structures "multilamellar smectic mesophases," or sometimes "Banghasomes," Weissmann proposed the more user-friendly term liposome.[16][17]
A liposome has an aqueous solution core surrounded by ahydrophobic membrane, in the form of alipid bilayer;hydrophilicsolutes dissolved in the core cannot readily pass through the bilayer. Hydrophobic chemicals associate with the bilayer. This property can be utilized to load liposomes with hydrophobic and/or hydrophilic molecules, a process known as encapsulation.[18] Typically, liposomes are prepared in a solution containing the compound to be trapped, which can either be an aqueous solution for encapsulating hydrophilic compounds like proteins,[19][20] or solutions in organic solvents mixed with lipids for encapsulating hydrophobic molecules.Encapsulation techniques can be categorized into two types: passive, which relies on the stochastic trapping of molecules during liposome formation, and active, which relies on the presence of charged lipids or transmembrane ion gradients.[18]A crucial parameter to consider is the "encapsulation efficiency," which is defined as the amount of compound present in the liposome solution divided by the total initial amount of compound used during the preparation.[21]In more recent developments, the application of liposomes insingle-molecule experiments has introduced the concept of "single entity encapsulation efficiency." This term refers to the probability of a specific liposome containing the required number of copies of the compound.[22]
To deliver the molecules to a site of action, the lipid bilayer can fuse with other bilayers such as thecell membrane, thus delivering the liposome contents; this is a complex and non-spontaneous event, however,[23] that does not apply to nutrients and drug delivery. By preparing liposomes in a solution ofDNA ordrugs (which would normally be unable todiffuse through the membrane) they can be (indiscriminately) delivered past the lipid bilayer.[24] 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 becharged in solution (i.e., the pH is outside the drug'spI 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 bydiffusion 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.[citation needed]
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.[25]Another strategy for liposome drug delivery is to targetendocytosis events. Liposomes can be made in a particular size range that makes them viable targets for naturalmacrophagephagocytosis. These liposomes may bedigested while in the macrophage'sphagosome, thus releasing its drug. Liposomes can also be decorated withopsonins andligands to activate endocytosis in other cell types.[citation needed]
To improve the tolerability of amphotericin and reduce toxicity, researchers developed several lipid formulations. Liposomal formulations have been found to have less renal toxicity than deoxycholate. and fewer infusion-related reactions.
AmBisome (liposomal amphotericin B; LAMB) is a liposomal formulation of amphotericin B forinjection and consists of a mixture ofphosphatidylcholine,cholesterol and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange intounilamellar vesicles that contain amphotericin B. It was developed by NeXstar Pharmaceuticals (acquired byGilead Sciences in 1999). It was approved by the FDA in 1997. It is marketed by Gilead in Europe and licensed toAstellas Pharma (formerly Fujisawa Pharmaceuticals) for marketing in the US, andSumitomo Pharmaceuticals in Japan.[56][57][58]
Regarding pH-sensitive liposomes, there are three mechanisms of drug delivery intracellularly, which occurs via endocytosis.[26] This is possible because of the acidic environment within endosomes.[26] The first mechanism is through the destabilization of the liposome within the endosome, triggering pore formation on the endosomal membrane and allowing diffusion of the liposome and its contents into the cytoplasm.[26] Another is the release of the encapsulated content within the endosome, eventually diffusing out into the cytoplasm through the endosomal membrane.[26] Lastly, the membrane of the liposome and the endosome fuse together, releasing the encapsulated contents onto the cytoplasm and avoiding degradation at the lysosomal level due to minimal contact time.[26]
Certain anticancer drugs such asdoxorubicin (Doxil) anddaunorubicin may be administered encapsulated in liposomes. Liposomalcisplatin has receivedorphan drug designation for pancreatic cancer from EMEA.[27] A study provides a promising preclinical demonstration of the effectiveness and ease of preparation ofvalrubicin-loaded immunoliposomes (Val-ILs) as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death.[28]
The use of liposomes for transformation ortransfection of DNA into a host cell is known aslipofection.
In addition to gene and drug delivery applications, liposomes can be used as carriers for the delivery of dyes to textiles,[29] pesticides to plants, enzymes and nutritional supplements to foods, and cosmetics to the skin.[30]
Liposomes are also used as outer shells of some microbubblecontrast agents used incontrast-enhanced ultrasound.
Until recently, the clinical uses of liposomes were fortargeted drug delivery, but new applications for the oral delivery of certain dietary and nutritional supplements are in development.[31] This new application of liposomes is in part due to the low absorption andbioavailability rates of traditional oral dietary and nutritional tablets and capsules. The low oral bioavailability and absorption of many nutrients is clinically well documented.[32] Therefore, the natural encapsulation oflypophilic andhydrophilic nutrients within liposomes would be an effective method of bypassing the destructive elements of thegastric system andsmall intestines allowing the encapsulated nutrient to be efficiently delivered to the cells and tissues.[33]
The termnutraceutical combines the wordsnutrient andpharmaceutical, 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".[34] 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.[35] 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, includingvitamins,minerals,amino acids,essential fatty acids,fibres 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.[36]
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.[37] They are the following: (1) The actual manufacturing method and preparation of the liposomes themselves; (2) The constitution, quality, and type of rawphospholipid 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.
The choice of liposome preparation method depends, i.a., on the following parameters:[38][39]
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.[5][24]
Liposomes can hence be created bysonicating a dispersion of amphipatic lipids, such asphospholipids, in water.[8] Lowshear rates create multilamellar liposomes. The original aggregates, which have many layers like an onion, thereby form progressively smaller and finallyunilamellar 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[40][41][42] and Mozafari method[43] are employed to produce materials for human use. Using lipids other thanphosphatidylcholine can greatly facilitate liposome preparation.[5]
Further advances in liposome research have been able to allow liposomes to avoid detection by the body's immune system, specifically, the cells ofreticuloendothelial system (RES). These liposomes are known as "stealth liposomes". They were first proposed by G. Cevc and G. Blume[44] and, independently and soon thereafter, the groups of L. Huang andVladimir Torchilin[45] and are constructed with PEG (Polyethylene Glycol) studding the outside of the membrane. The PEG coating, which isinert 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.[46][47] 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 bemonoclonal antibodies (making animmunoliposome),vitamins, or specificantigens, but must be accessible.[48] 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 astransfersomes.[49]
Liposomes are used as models for artificial cells.
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.[50]
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.[51][52]
Machine learning has started to contribute to liposome research. For example,deep learning was used to monitor a multistepbioassay containing sucrose-loaded and nucleotides-loaded liposomes interacting with a lipid membrane-perforatingpeptide.[53]Artificial neural networks were also used to optimize formulation parameters ofleuprolideacetate loaded liposomes[54]and to predict the particle size and thepolydispersity index of liposomes.[55]
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