Liposome
A liposome ( Greek. Lipos , fat 'and soma , body', plural: liposome) is a bubble ( vesicles ) that includes an aqueous phase and whose membrane envelope of a double layer of molecules is that (both a non-polar lipophilic , fat loving ) , as well as have a polar ( hydrophilic , water-loving ) part and are thus referred to as amphiphilic . The membrane-forming molecules are usually substances from the lipid class , such as phospholipids and fatty acids . Liposomes serve as a model for the investigation of the biophysical properties of biomembranes and are also used in the cosmetic, and above all in the medical field ( drug targeting ). Liposomes are to be distinguished from micelles , which only have a simple lipid layer.
discovery
Liposomes were first discovered and described in 1964 by a working group at the Babraham Institute headed by the British hematologist Alec Douglas Bangham. The name "liposome" can be traced back to Gerald Weissmann, who was also significantly involved in the discovery and research of liposomes. The publication " Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope " published in 1964 by Alec Douglas Bangham and RW Horne in the Journal of Molecular Biology is considered to be the publication in which liposomes (then still as “ Multilamellar smectic mesophases ” ) were first mentioned.
Structure and properties
The membrane-forming molecules of a liposome have a hydrophilic / lipophobic and a hydrophobic / lipophilic part. When forming the bilayer of the liposome, these amphiphilic molecules arrange themselves according to these properties. The hydrophobic parts of the molecules are directed towards each other so that they have little contact with the aqueous phase, whereas the hydrophilic parts of the molecules are directed towards the aqueous phase inside and outside the liposome. This behavior is based on the formation of an energetically favorable spherical shape with the smallest possible surface area ( hydrophobic effect ). The membrane's molecules hold together through non-covalent interaction. This results in a fluid membrane, the aliphatic , lipophilic interior of which is receptive to the absorption of a large number of lipophilic substances.
The size and shape of liposomes are fundamentally dependent on the chemical composition of the lipid membrane, the physico-chemical properties of the aqueous phase (e.g. ionic strength , pH value , osmolality ) in which they are present or which they contain and the preparation process (see Manufacture ). Liposomes can be single-layer (a double layer, unilamellar) or multilayer (several concentric double layers, multilamellar) and have an average diameter of 25 nm to 100 µm. Using these two parameters, size (mean diameter) and lamellarity, liposomes can be roughly divided into four categories.
M ulti l amellar v esicles (MLV) generally consist of several concentric lipid bilayers. Their mean diameter is between 100 nm and 1000 nm. S mall u nilamellar v esicles (SUV) are unilamellar and have a mean diameter between 20 nm and 100 nm, whereas l arge u nilamellar v esicles (LUV) and g iant u nilamellar v esicles (GUV) have a diameter between 100 nm and 1000 nm or between 1 µm and 200 µm. The larger liposomes can therefore be seen in visible light with a light microscope .
The membrane of a liposome can be composed of various lipids. Depending on the desired pharmacodynamic action profile, pharmacokinetic behavior, chemical and physical properties such as size, size distribution, lamellarity, fluidity , permeability , zeta potential , phase transition temperature of the membrane and much more, liposomes for medical and cosmetic applications can be prepared from a wide range of diverse lipids from the substance classes of Phospholipids and sterols can be chosen. The lipids from these two classes of substances are primarily structural components of the liposome. In addition, lipopolysaccharides (e.g. lipid A as an adjuvant ), fatty acids and other lipophilic substances such as B. tocopherols (as antioxidants ) and squalene as membrane components are used.
The first stage of development of living cells in the primordial soup were probably liposome-like structures that formed spontaneously from amphiphilic lipids (for example from phosphatidylcholine lecithin ) in an aqueous medium.
Applications
Due to the liposomal formulation of medicinal substances, it is possible by means of inclusion immobilization to protect sensitive medicinal substances from possible metabolism after application . Similarly, niosomes are used. In addition, the inclusion of drugs in liposomes can increase the plasma half-life . Liposomes as a drug delivery system can improve the transport of drugs to those places in the organism where they are needed. As a result, side effects of the liposomally formulated drug can be reduced and, since lower doses can be administered, the efficiency and the therapeutic index can be increased. A liposomal formulation is open to most drugs because of the properties of the liposome. Hydrophilic drugs are enclosed and are located in the hydrophilic interior of the liposome. Lipophilic drugs are embedded in the membrane and amphiphilic drugs at the interface between the interior of the membrane and the aqueous phase. Liposomal formulations of drugs such as biopharmaceuticals , which include vaccines such as siRNA and miRNA for applications in therapeutic RNA interference , but also of non-biological synthetic drugs, bring pharmacological and economic advantages.
Virosomes , i.e. liposomes that carry viral coat proteins in their lipid membrane , serve both as a system for targeted and selective transport and as an adjuvant. Virosomes that are absorbed into cells through the endosome membrane after endocytosis also have the property of being able to trigger both a humoral immune response and a cellular immune response .
In some pharmaceutical products, the liposomes also have to be protected by a superficial polymer layer (typically made of polyethylene glycol) to prevent them from fusing with any random cell membrane (usually in the liver ) before the active ingredient has reached its destination. On the way to their destination, the active ingredients enclosed in a liposome can be protected against the destructive effects of enzymes and from premature elimination from the body by the lipid bilayer . With the help of foreign molecules (such as antibodies ) that are attached to the exterior of the liposomes, one can also try to determine the exact destination of the active ingredient by binding to a specific receptor ( drug targeting ). Due to their cell membrane-like chemical nature, liposomes can presumably easily fuse with the cell membrane or, after pinocytosis or endocytosis , with the endosome and lysosome membrane and then release their contents into the cell interior .
In biotechnology, liposomes are sometimes used to introduce foreign material, for example plasmids , into a cell. This process is known as liposomal transfection or lipofection , but has only been poorly understood to date and is also much less effective than transduction using a viral vector .
As an alternative to liposomes, polymersomes are also used.
Essential nutrients and food supplements, especially those with a normally slow, regulated or only partial absorption mechanism, such as vitamin C , can also get better into the bloodstream when enclosed in liposomes. For some functional natural substances such as curcumin , whose bioavailability is low due to their hydrophobicity, a significant increase in bioavailability through liposomes has been demonstrated. A human study comparing the effects of orally administered vitamin C in enclosed and non-enclosed form versus intravenous administration concluded that (1) the concentration of liposomal vitamin C circulating in the blood was greater than that of the orally administered, non-enclosed vitamin Variant. However, the amount detected in the blood was still lower than after intravenous administration. (2) The measured ischemic reperfusion value determined as a marker for oxidative stress was similarly reduced between all administration forms.
Manufacturing
Multilamellar liposomes (MLV) are formed spontaneously by dissolving lipids in the aqueous phase. Unilamellar liposomes (SUV / LUV) can be generated by various methods.
Liposomal finished medicinal products
As of 2008, 11 drugs had been approved in liposomal administration.
| Examples of liposomal finished drugs | ||||
|---|---|---|---|---|
| Active ingredient | Trade name | Pharmaceutic entrepreneur | Type of liposomes | Application areas) |
| Amphotericin B | Abelcet ("worldwide") | Cephalon , Teva | Lipid lamellae | Systemic fungal infections |
| AmBisome (various European countries, TR, CDN, USA) | Gilead Sciences , Astellas | Conventional liposomes | ||
| Cytarabine | DepoCyte (EU, CH) | Pacira Limited | Multivesicular liposomes | Malignant lymphomatous meningiosis |
| Daunorubicin | DaunoXome (GB, DE, DK) | Gilead Sciences | HIV-associated Kaposi's sarcoma | |
| Doxorubicin | Myocet ("worldwide") | Teva | Conventional liposomes | Metastatic breast cancer |
| Doxil (USA) / Caelyx ("worldwide" except USA) | Janssen-Cilag | PEG -ylated liposomes | Breast cancer , ovarian cancer , HIV-associated Kaposi's sarcoma, multiple myeloma | |
| Morphine | DepoDur (USA) | SkyePharma, Endo | Multivesicular liposomes | Post-operative analgesia |
| Hepatitis A vaccine | Epaxal / HAVpur | Berna Biotech , Novartis | Virosomes | Hepatitis A |
| Influenza vaccine | Inflexal V / Influvac | Berna Biotech, Novartis | Virosomes | Influenza |
| Paclitaxel | Lipusu (CN) | Luye Pharma | Conventional liposomes | Ovarian cancer |
| Floods | Definity (USA) | Lantheus | Ultrasound contrast | |
| Verteporfin | Visudyne (EU, CH, J, USA) | Novartis | Wet age-related macular degeneration , pathological myopia | |
The importance of liposomal drug formulations for drug targeting, especially in indications such as cancer or infections in cystic fibrosis, is evident in a significant number of corresponding formulations among orphan drugs .
literature
- RRC New (Ed.): Liposomes a practical approach. IRL Press at Oxford University Press, Oxford 1990, ISBN 0-19-963077-1 .
- Dietrich Arndt, Iduna Fichtner: Liposomes: Presentation - Properties - Application. (= Advances in Oncology. Volume 13). Akademie-Verlag, Berlin 1986, ISBN 3-05-500148-6 .
- Volker Weissig (Ed.): Liposomes: Methods and Protocols. Volume 1: Pharmaceutical nanocarriers. (= Methods in Molecular Biology. Volume 605). Humana Press, New York 2010, ISBN 978-1-60327-360-2 .
- Volker Weissig (Ed.): Liposomes: Methods and Protocols. Volume 2: Biological Membrane Models. (= Methods in Molecular Biology. Volume 606). Humana Press, New York 2010, ISBN 978-1-60761-446-3 .
- Shelley D. Minteer (Ed.): Enzyme Stabilization and Immobilization: Methods and Protocols. (= Methods in Molecular Biology. Volume 679). Humana Press, Totowa NJ 2011, ISBN 978-1-60761-895-9 .
Web links
Individual evidence
- ↑ VP Torchilin: targeting drug. In: European Journal of Pharmaceutical Sciences . 11, Supplement 2, 2000, pp. S81-S91.
- ↑ David W. Deamer: From “Banghasomes” to liposomes: A memoir of Alec Bangham, 1921-2010 . In: FASEB J . 24, 2010, pp. 1308-1310.
- ↑ Grazia Sessa, Gerald Weissmann: Phospholipid spherules (liposomes) as a model for biological membranes. In: Journal of Lipid Research. Volume 9, No. 3, 1968, pp. 310-318.
- ^ AD Bangham, RW Horne: Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope. In: Journal of Molecular Biology . Volume 8, Issue 5, 1964, pp. 660-668.
- ↑ Emeline Rideau, Rumiana Dimova, Petra Schwille, Frederik R. Wurm, Katharina Landfester: Liposomes and polymersomes: a comparative review towards cell mimicking . In: Chemical Society Reviews . tape 47 , no. 23 , 2018, ISSN 0306-0012 , p. 8572–8610 , doi : 10.1039 / C8CS00162F ( rsc.org [accessed September 20, 2019]).
- ↑ Ala Daka, Dan Peer: RNAi-based nanomedicines for targeted personalized therapy. In: Advanced Drug Delivery Reviews . Volume 64, Issue 13, October 2012, pp. 1508–1521.
- ↑ Yasufumi Kaneda: Virosomes: evolution of the liposome as a targeted drug delivery system . In: Advanced Drug Delivery Reviews . tape 43 , no. 2–3 , September 30, 2000, pp. 197-205 , doi : 10.1016 / S0169-409X (00) 00069-7 ( sciencedirect.com ).
- Jump up ↑ A. Wagner, G. Stiegler, K. Vorauer-Uhl, H. Katinger, H. Quendler, A. Hinz, W. Weissenhorn: One Step Membrane Incorporation of Viral Antigens as a Vaccine Candidate Against HIV. In: Journal of Liposome Research . Volume 17, 2007, pp. 139-154.
- ↑ JC Kraft, JP Freeling, Z. Wang, RJ Ho: Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems . In: J Pharm Sci. tape 103 , no. 1 , 2014, p. 29-52 .
- ↑ J. Shaikh, DD Ankola, V. Beniwal, D. Singh, MN Kumar: Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. In: Eur J Pharm Sci. No. 37 , 2009, p. 223-230 .
- ↑ Janelle L. Davis, Hunter L. Paris, Joseph W. Beals, Scott E. Binns, Gregory R. Giordano, Rebecca L. Scalzo, Melani M. Schweder, Emek Blair, Christopher Bell: Liposomal-encapsulated Ascorbic Acid: Influence on Vitamin C Bioavailability and Capacity to Protect Against Ischemia – Reperfusion Injury . In: Nutr Metab Insights. No. 9 , June 20, 2016, p. 25-30 .
- ↑ a b L. Zhang, FX Gu, JM Chan, AZ Wang, RS Langer, OC Farokhzad: Nanoparticles in Medicine: Therapeutic Applications and Developments . In: Clinical Pharmacology and Therapeutics . Vol. 83, No. 5 , 2008, p. 761-769 , doi : 10.1038 / sj.clpt.6100400 , PMID 17957183 ( nature.com ).
- ^ R. Schubert: Liposomes. In: U. Weidenauer, K. Mäder (Hrsg.): Innovative drug forms. Wissenschaftliche Verlagsgesellschaft, October 2009, p. 162.
- ^ Rare disease (orphan) designations , accessed February 4, 2013.