Liposomes are artificially prepared vesicles made of lipid bilayer. Liposomes can be filled with drugs, and used to deliver drugs for cancer and other diseases.[1] Liposomes are composite structures made of phospholipids and may contain small amounts of other molecules. Though liposomes can vary in size from low micrometer range to tens of micrometers, unilamellar liposomes, as pictured here, are typically in the lower size range with various targeting ligands attached to their surface allowing for their surface-attachment and accumulation in pathological areas for treatment of disease.[2] Liposomes can be prepared by disrupting biological membranes, for example by sonication.
Liposomes can be composed of naturally derived phospholipids with mixed lipid chains (like egg phosphatidylethanolamine) or other surfactants. Liposomes should not be confused with micelles and reverse micelles composed of monolayers.[3]
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The name liposome is derived from two Greek words: 'LIPO' meaning fat and 'Soma' meaning body. A liposome can be formed at a variety of sizes as uni-lamellar or multi-lamellar construction, and its name relates to its structural building blocks, phospholipids, and not to its size. In contrast, the term Nanosome does relate to size and was coined in the early 1990s to denote special liposomes in the low nanometer range; liposome and Nanosome are not synonyms. A liposome does not necessarily have lipophobic contents, such as water, although it usually does.
Liposomes were first described by British haematologist Dr Alec D Bangham[4][5][6] 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 by adding negative stain to dry phospholipids. The resemblance to the plasmalemma was obvious, and the microscope pictures served as the first real evidence for the cell membrane being a bilayer lipid structure.
Liposomes are used for drug delivery due to their unique properties. A liposome encapsulates a region of aqueous solution inside a hydrophobic membrane; dissolved hydrophilic solutes cannot readily pass through the lipids. Hydrophobic chemicals can be dissolved into the membrane, and in this way liposome can carry both hydrophobic molecules and hydrophilic molecules. To deliver the molecules to sites of action, the lipid bilayer can fuse with other bilayers such as the cell membrane, thus delivering the liposome contents. By making liposomes in a solution of DNA or drugs (which would normally be unable to diffuse through the membrane) they can be (indiscriminately) delivered past the lipid bilayer. There are three types of liposomes - MLV (multilamellar vesicles) SUV (Small Unilamellar Vesicles) and LUV (Large Unilamellar Vesicles). These are used to deliver different types of drugs.
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.
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.[7] Another strategy for liposome drug delivery is to target endocytosis events. Liposomes can be made in a particular size range that makes them viable targets for natural macrophage phagocytosis. These liposomes may be digested while in the macrophage's phagosome, thus releasing its drug. Liposomes can also be decorated with opsonins and ligands to activate endocytosis in other cell types.
In addition to gene and drug delivery applications, liposomes can be used as carriers for the delivery of dyes to textiles,[8] pesticides to plants, enzymes and nutritional supplements to foods, and cosmetics to the skin.[9]
Liposomes are also used as outer shells of some microbubble contrast agents used in contrast-enhanced ultrasound.
As of 2008, 11 drugs with liposomal delivery systems have been approved and 6 additional liposomal drugs were in clinical trials.[10]
List of clinically approved liposomal drugs
| Name | Trade name | Company | Indication |
| Liposomal amphotericin B | Abelcet | Enzon | Fungal infections |
| Liposomal amphotericin B | Ambisome | Gilead Sciences | Fungal and protozoal infections |
| Liposomal cytarabine | Depocyt | Pacira (formerly SkyePharma) | Malignant lymphomatous meningitis |
| Liposomal daunorubicin | DaunoXome | Gilead Sciences | HIV-related Kaposi’s sarcoma |
| Liposomal doxorubicin | Myocet | Zeneus | Combination therapy with cyclophosphamide in metastatic breast cancer |
| Liposomal IRIV vaccine | Epaxal | Berna Biotech | Hepatitis A |
| Liposomal IRIV vaccine | Inflexal V | Berna Biotech | Influenza |
| Liposomal morphine | DepoDur | SkyePharma, Endo | Postsurgical analgesia |
| Liposomal verteporfin | Visudyne | QLT, Novartis | Age-related macular degeneration, pathologic myopia, ocular histoplasmosis |
| Liposome-PEG doxorubicin | Doxil/Caelyx | Ortho Biotech, Schering-Plough | HIV-related Kaposi’s sarcoma, metastatic breast cancer, metastatic ovarian cancer |
| Micellular estradiol | Estrasorb | Novavax | Menopausal therapy |
Another interesting property of liposomes are their natural ability to target cancer. The endothelial wall of all healthy human blood vessels is encapsulated by endothelial cells that are bound together by tight junctions. These tight junctions stop any large particles in the blood from leaking out of the vessel. Tumour vessels do not contain the same level of seal between cells and are diagnostically leaky. This ability is known as the Enhanced Permeability and Retention effect. Liposomes of certain sizes, typically less than 200 nm, can rapidly enter tumour sites from the blood, but are kept in the bloodstream by the endothelial wall in healthy tissue vasculature. Anti-cancer drugs such as Doxorubicin (Doxil), Camptothecin and Daunorubicin (Daunoxome) are currently being marketed in liposome delivery systems.
New Liposomal drugs targeting cancer like Liposomal Cisplatin (Lipoplatin of Regulon Inc.) has received Orphan Drug designation for Pancreatic Cancer from EMEA.
Regarding the use of Liposomes as a carrier of dietary and nutritional supplements; until very recently the use of Liposomes were primarily directed at targeted drug delivery. However, the versatile abilities of Liposomes are now being discovered in other settings. Liposomes are presently being cleverly implemented for the specific oral delivery of certain dietary and nutritional supplements.[11]
A very small number of dietary and nutritional supplement companies are currently pioneering the benefits of this unique science towards this new application. This new direction and employment of Liposome science 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.[12] Therefore the natural encapsulation of lypophilic and hydrophilic nutrients within Liposomes has made for a very effective method of bypassing the destructive elements of the gastric system and aiding the encapsulated nutrient to be delivered to the cells and tissues.[13][14]
It is important to note that certain influential factors have far reaching effects on the percentage of Liposome that are yielded in manufacturing.[15] These influences also have an effect on the actual amount of realized Liposome entrapment and the actual quality of the Liposomes themselves. These are very crucial elements which lead to the long term stability of the Liposomes. These complex yet significant factors are the following: (1) The actual manufacturing method and preparation of the Liposomes themselves; (2) The constitution, quality, and type of raw phospholipid used in the formulation and manufacturing of the Liposomes; (3) The ability to create homogenous Liposome particle sizes that are stable and hold their encapsulated payload. These primary and key elements comprise the foundation of an effective Liposome carrier for use in increasing the bioavailability of oral dosages of dietary and nutritional supplements.[16]
Liposomes, which use a form nanotechnology science, also impressively and harmoniously, use the generalized nature of the Liposomes themselves to therefore increase the efficacy, bioavailability, absorption, and delivery of these certain entrapped dietary and nutritional supplements.[17] This generalized nature and makeup of Liposomes, being composed of phospholipids, adroitly complements the natural lining of nearly every cell within the human body.[18] This therefore creates a natural bond and or affinity for the Liposomes to deliver their onboard “payload” to the cells. The quality of raw Lipid used in the preparation and manufacturing of the Liposomes therefore precisely co-relates to this natural congruency between the Liposomes and the cells of the human body.[19]
The correct choice of liposome preparation method depends on the following parameters:[20][21]
Formation of liposomes and nanoliposomes is not a spontaneous process. Lipid vesicles are formed when phospholipids such as lecithin are placed in water and consequently form one bilayer or a series of bilayers, each separated by water molecules, once enough energy is supplied.[22] Liposomes can be created by sonicating phospholipids in water.[3] Low shear rates create multilamellar liposomes, which have many layers like an onion. Continued high-shear sonication tends to form smaller unilamellar liposomes. In this technique, the liposome contents are the same as the contents of the aqueous phase. 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 and Mozafari method [23] are employed to produce materials for human use.
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 liposomes", and are constructed with PEG (Polyethylene Glycol) studding the outside of the membrane. The PEG coating, which is inert in the body, allows for longer circulatory life for the drug delivery mechanism. However, research currently seeks to investigate at what amount of PEG coating the PEG actually hinders binding of the liposome to the delivery site. In addition to a PEG coating, most stealth liposomes also have some sort of biological species attached as a ligand to the liposome in order to enable binding via a specific expression on the targeted drug delivery site. These targeting ligands could be monoclonal antibodies (making an immunoliposome), vitamins, or specific antigens. Targeted liposomes can target nearly any cell type in the body and deliver drugs that would naturally be systemically delivered. Naturally toxic drugs can be much less toxic if delivered only to diseased tissues. Polymersomes, morphologically related to liposomes, can also be used this way.
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