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Liposomes for Use in Gene Delivery
ARTICLE JANUARY 2011
DOI: 10.1155/2011/326497 Source: PubMed
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WT Godbey
Tulane University
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Hindawi Publishing CorporationJournal of Drug DeliveryVolume 2011, Article ID 326497,12pagesdoi:10.1155/2011/326497
Review ArticleLiposomes for Use in Gene Delivery
Daniel A. Balazs and WT. Godbey
Laboratory for Gene Therapy and Cellular Engineering, Department of Chemical and Biomolecular Engineering,Tulane University, 6823 St. Charles Avenue, 300 Lindy Boggs Center, New Orleans, LA 70118, USA
Correspondence should be addressed to WT. Godbey,[email protected]
Received 30 June 2010; Accepted 29 October 2010
Academic Editor: Seyed Moein Moghimi
Copyright 2011 D. A. Balazs and WT. Godbey. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.
Liposomes have a wide array of uses that have been continuously expanded and improved upon since first being observed to self-assemble into vesicular structures. These arrangements can be found in many shapes and sizes depending on lipid composition.Liposomes are often used to deliver a molecular cargo such as DNA for therapeutic benefit. The lipids used to form such lipoplexescan be cationic, anionic, neutral, or a mixture thereof. Herein physical packing parameters and specific lipids used for gene deliverywill be discussed, with lipids classified according to overall charge.
1. Introduction
Liposomes are vesicular structures that can form via theaccumulation of lipids interacting with one another in anenergetically favorable manner. Depending upon the struc-ture and the composition of the bulk solution, liposomescan separate hydrophobic or hydrophilic molecules from thesolution. These vesicles are not rigid formations but ratherare fluid entities that are versatile supramolecular assemblies.Because they have dynamic properties and are relativelyeasy to manipulate, liposomes have been used widely in theanalytical sciences as well as for drug and gene delivery.Since their first published use in 1965[1,2],the value andpracticality of liposome functions have been recognized and
continually improved upon.The advances that brought about liposome-derived tech-
nologies have been recognized as some of the cornerstones ofbionanotechnology [3]. The unique advantages imparted bylipid vesicles are their diverse range of morphologies, compo-sitions, abilities to envelope and protect many types of ther-apeutic biomolecules, lack of immunogenic response, lowcost, and their differential release characteristics[46].Thesecharacteristics have led to applications in chemical and bio-chemical analytics, cosmetics, food technologies, and drugand gene delivery [7,8]. There are numerous lipid formula-tions for each of these applications. However, this review willfocus primarily on the use of liposomes for gene delivery.
2. Characteristics
Liposomes are generally formed by the self-assembly of dis-solved lipid molecules, each of which contains a hydrophilichead group and hydrophobic tails. These lipids take onassociations which yield entropically favorable states of lowfree energy, in some cases forming bimolecular lipid leaflets(Figure 1). Such leaflets are characterized by hydrophobichydrocarbon tails facing each other and hydrophilic headgroups facing outward to associate with aqueous solution[9].At this point, the bilayer formation is still energeticallyunfavorable because the hydrophobic parts of the moleculesare still in contact with water, a problem that is overcomethrough curvature of the forming bilayer membrane upon
itself to form a vesicle with closed edges [10] (Figure 1).This free-energy-driven self-assembly is stable and hasbeen exploited as a powerful mechanism for engineeringliposomes specifically to the needs of a given system [11].
Lipid molecules used in liposomes are conserved entitieswith a head group and hydrophobic hydrocarbon tailsconnected via a backbone linker such as glycerol [12].Cationic lipids commonly attain a positive charge throughone or more amines present in the polar head group. Thepresence of positively charged amines facilitates binding withanions such as those found in DNA. The liposome thusformed is a result of energetic contributions by Van der Waalsforces and electrostatic binding to the DNA which partially
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protected]://www.researchgate.net/publication/17327192_Bangham_AD_Standish_MM_Watkins_JCDiffusion_of_univalent_ions_across_the_lamellae_of_swollen_phospholipids_J_Mol_Biol_13_238-252?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/17327192_Bangham_AD_Standish_MM_Watkins_JCDiffusion_of_univalent_ions_across_the_lamellae_of_swollen_phospholipids_J_Mol_Biol_13_238-252?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/17327192_Bangham_AD_Standish_MM_Watkins_JCDiffusion_of_univalent_ions_across_the_lamellae_of_swollen_phospholipids_J_Mol_Biol_13_238-252?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/17327192_Bangham_AD_Standish_MM_Watkins_JCDiffusion_of_univalent_ions_across_the_lamellae_of_swollen_phospholipids_J_Mol_Biol_13_238-252?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/17327192_Bangham_AD_Standish_MM_Watkins_JCDiffusion_of_univalent_ions_across_the_lamellae_of_swollen_phospholipids_J_Mol_Biol_13_238-252?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/42832762_Gene_delivery_by_lipoplexes_and_polyplexes_Eur_J_Pharm_Sci?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/42832762_Gene_delivery_by_lipoplexes_and_polyplexes_Eur_J_Pharm_Sci?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/42832762_Gene_delivery_by_lipoplexes_and_polyplexes_Eur_J_Pharm_Sci?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/42832762_Gene_delivery_by_lipoplexes_and_polyplexes_Eur_J_Pharm_Sci?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/42832762_Gene_delivery_by_lipoplexes_and_polyplexes_Eur_J_Pharm_Sci?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/20702748_Equilibrium_and_non-equilibrium_approaches_in_biomembrane_thermodynamics?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/20702748_Equilibrium_and_non-equilibrium_approaches_in_biomembrane_thermodynamics?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/20702748_Equilibrium_and_non-equilibrium_approaches_in_biomembrane_thermodynamics?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/11078926_Shape_behavior_of_lipid_vesicles_as_the_basis_of_some_cellular_processes?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/11078926_Shape_behavior_of_lipid_vesicles_as_the_basis_of_some_cellular_processes?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/11078926_Shape_behavior_of_lipid_vesicles_as_the_basis_of_some_cellular_processes?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/223806134_Bottom-up_strategy_of_materials_fabrication_a_new_trend_in_nanotechnology_of_soft_materials_Curr_Opin_Colloid_Interface_Sci_611-16?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9c3a-c97a7f34e8b3&enrichSource=Y292ZXJQYWdlOzUxMDQ5MTE2O0FTOjEwMTM2MTgzMjE2OTQ5MEAxNDAxMTc3OTUyOTQ0https://www.researchgate.net/publication/223806134_Bottom-up_strategy_of_materials_fabrication_a_new_trend_in_nanotechnology_of_soft_materials_Curr_Opin_Colloid_Interface_Sci_611-16?el=1_x_8&enrichId=rgreq-e6285153-ec41-4e1a-9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Figure1: Certain amphipathic lipid molecules in aqueous solution spontaneously form leaflets, then bilayer membranes, and eventuallyliposomes.
dictates liposome shapes [13]. Because of the polyanionicnature of DNA, cationic (and neutral) lipids are typically
used for gene delivery, while the use of anionic liposomeshas been fairly restricted to the delivery of other therapeuticmacromolecules[14].
Liposomes can exhibit a range of sizes and morphologiesupon the assembly of pure lipids or lipid mixtures suspendedin an aqueous medium [2]. A common morphology whichis analogous to the eukaryotic cellular membrane is the unil-amellar vesicle. This vesicle is characterized by a single bilayermembrane which encapsulates an internal aqueous solution,thus separating it from the external (bulk) solution [15].Both cationic amine head groups and anionic phospholipidhead groups can form these single-walled vesicles. Vesiclesizes fall into the nanometer to micrometer range: small
unilamellar vesicles are 20200 nm, large unilamellar vesiclesare 200 nm1 m, and giant unilamellar vesicles are largerthan 1 m[2].
Giant vesicles also include other morphologies suchas multilamellar, which consists of multiple concentricbilayers, oligolamellar, which consists of only two concentricbilayers, and multivesicular, which consists of multiplesmaller unilamellar vesicles inside of one giant one. With theexception of multilamellar vesicles, these other morphologiesare difficult to obtain without highly controlled processes forformation [2]. Giant vesicles also deserve special attentionbecause their sizes are large, ranging from 1 m to morethan 100 m [2]. These large vesicles are studied and wellcharacterized, partially due to the ease of observation viaoptical microscopy[10].
During the compaction of polynucleotides into liposo-mal assemblies, a number of structures have been knownto appear [5, 6, 1619]. Each structure is formed in themost energetically favorable conformation based upon char-acteristics of the specific lipids used in the system [13]. Adependent term known as the structure-packing parametercan be used to suggest what shape the amphiphile willtake, depending on the ratio of size variables. The packingparameter is defined as
P=v
alc, (1)
where v: the volume of the hydrocarbon portion, a: theeffective area of the head group, andlc: the length of the lipid
tail.This correlation predicts a range of structures accordingto the following conditions[13,20](Figure 2):
P