introduction into cubic phase lipids
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Introduction Into Cubic Phase Lipids. Matt Chandler. Polymorphism . In general, it describes multiple possible states for a single property. Also known as mesomorphism. Ex. Carbon can exist as diamond or graphite. . Polymorphism in Lipids.

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  • In general, it describes multiple possible states for a single property.
  • Also known as mesomorphism.
  • Ex. Carbon can exist as diamond or graphite.
polymorphism in lipids
Polymorphism in Lipids
  • The ability of a given mixture of lipids to form crystallographically diverse structures.

A - lamellar liquid crystal phase, L.

B - inverted hexagonal phase, HII.

C - hexagonal phase, HI.

why study lipid polymorphs
Why Study Lipid Polymorphs?
  • They exhibit the broadest range of polymorphic structures of any known class of molecules.
  • By studying the structural polymorphism observed with isolated lipids, we can gain an understanding of the forces that are locked up in biomembranes and that affect the organization and function of proteins.
  • Non-Bilayer Phase - nonlamellar phase, or liquid crystalline phases that are not L phases.
  • Inverted or Water-In-Oil Phase - refers to one in which the lipid/water interface has the same sign curvature as an HII phase, i.e. a net concave curvature when viewed from the water domain.
  • Liquid-Crystalline - refers to phases that are intermediate to the rigorously crystalline solids and true isotopic liquids, including systems that do not have long flexible chains.
lipid phases
Lipid Phases
  • We try to understand the physical basis of lipid phases, because an understanding of this basis gives insight into the forces at play in lipid bilayers.
  • A polar biomembranes lipid interaction with water allows for a variety of structures, or polymorphs, not normally found in cells.
  • These include, lipid bilayers, as well as tubes, rods (hexagonal phases), and three dimensional assemblies, aka cubic phase lipids.
lamellar crystalline phase l
Lamellar Crystalline Phase, L

Bilayer (cylindrical).

  • Composed of lipid molecules, usually phospholipids.
  • These phospholipids have glycerol backbones with polar head groups and long hydrocarbon, hydrophobic tails.
inverted hexagonal phase h ii
Inverted Hexagonal Phase, HII
  • Reverse micelle aggregates that form tubes and rods.
  • Concave curvature.
  • Precipitates out of an aqueous solution.
hexagonal phase h i
Hexagonal Phase, HI
  • Tubular micelle aggregates.
  • Convex curvature.
  • Will suspend in aqueous solution.
  • Mostly comprised of lysophospholipids (monoacyl).

Snapshot of a configuration of lipid aggregates in the form of a filament of rod-like micelles formed by H3(T5)2 lipids and simulated by dissipative particle dynamics. The model parameters are adapted from Groot and Rabone (2001). The red beads represent hydrophilic head groups (H) and the green beads represent the tail beads (T). For the sake of clarity, the water beads are not shown.

cubic phase lipids
Cubic Phase Lipids
  • Cubic phases have an interesting thermodynamically stable structure consisting of curved bicontinuous lipid bilayer in three dimensions, separating two congruent networks of water channels.
  • It is suggested that the cubic phase is an intermediate of a phase transition between hex II and the lamellar phase, and is stabilized at a particular temperature.
  • Spontaneously formed when amphiphilic lipids are placed in aqueous environments.
most common lipids in clp
Most Common Lipids in CLP
  • Common cubic phase lipids:
  • 1-monooleoyl-rac-glycerol (MO)
  • 1-monopalmitoleoyl-rac-glycerol (MP)
  • Palmitoyl lysophosphatidylcholine (PLPC)
cubic phase lipids cont
Cubic Phase Lipids (Cont.)
  • CLPs have been studied extensively, however, this has proven to be difficult both due to the structural complexity and because crystallographically well-formed samples are difficult to obtain.
  • Crystallographic structures are difficult to obtain due to the low enthalpies associated with bicontinuous cubic transitions.
  • This suggests that the formation of cubic phases is not strongly favored and involves large energy of activation barriers.
cubic phase lipids cont13
Cubic Phase Lipids (Cont.)
  • Take on a PMS topology, or periodic minimal surface, which is a three-dimensional surface that periodically has zero mean curvature (H=0) everywhere.
  • Since the surface topology has a PMS-like structure, the cubic phase is in between the L phase (H=0) and the HII phase (H is large), using mean curvatures.
  • Most cubic PMS structures are just lipid monolayers that drape both sides of PMS-like structures, which is why they are classified as nonlamellar.
3 common motifs space groups
3 Common Motifs (Space Groups)
  • Primitive P, Im3m
  • Double diamond D, Pn3m
  • Gyroid G, Ia3d
purpose and uses
Purpose and Uses
  • These cubic phases are being used to grow well-ordered, three dimensional crystals of smaller membrane proteins.
  • Understanding the mechanisms of membrane proteins requires the elucidation of their structures to high resolution.
purpose and uses cont
Purpose and Uses (Cont.)
  • The complexity of the cubic phase allows for nucleation sites, or seeding sites, for membrane proteins to integrate and support growth by lateral diffusion of protein molecules in the membrane. This is known as feeding.
  • Proteins, once integrated, tend to aggregate toward the valley of the cubic phase matrix. This population increase allows for the crystallization of smaller membrane proteins.

Bacteriorhodopsin crystal obtained in the cubic-lipid phase (Pebay-Peyroula et al., Science 97, Belrhali et al., Structure 99).

purpose and uses cont17
Purpose and Uses (Cont.)
  • Cubic phase lipids have also been used on a nanometer level as a drug delivery mechanism.
  • Cubic phases have been shown to deliver small molecule drugs and large proteins by oral and parenteral routes in addition to local delivery in vaginal and periodontal cavity.
  • Release of drugs from cubic phase typically show diffusion controlled release from a matrix as indicated by Higuchi's square root of time release kinetics (international journal of pharmaceutics. Volume 160, issue 2, 26 January 1998, pages 207-212).
purposes and uses cont
Purposes and Uses (Cont.)
  • Incorporation of drug in cubic phase can cause phase transformation to lamellar or inverted hexagonal phase depending on the polarity and concentration of the drug, which could also affect the delivery.
why clp is good for drug delivery
Why CLP Is Good for Drug Delivery
  • Biodegradability.
  • Phase behavior.
  • Ability to deliver drugs of different size and polarity.
  • Ability to enhance chemical/physical stability of drugs or proteins.
  • Shorter release duration and the extremely high viscosity may limit CLPs use to specific applications such as periodontal, mucosal, vaginal and short acting oral and parenteral drug delivery.
  • A new potential application of the cubic phase (monoolein/water; 70:30, w/w) which is being studied, involves delivering pro-drugs and a photosensitizer for topical application in photodynamic therapy (PDT).
  • Crystallization efforts will continue as well.
  • Yeagle, P. (2005 ).The Structure of Biological Membranes (2nd. Ed.). Philadelphia: CRC Press.
  • Landau, E. M. and Rosenbusch, J.P. (1996). Lipidic Cubic Phases: A novel concept for the crystallization of membrane proteins. PNAS, 93(25), 14532-14535.
  • Seddon, J. M. and Conn, C. (2003). Pressure-jump Studies of Liquid-crystalline Cubic Phase Transition in Lipids.University of Dortmund, Germany.
  • Grabe, M. and Neu, J. (2003). Protein Interactions and Membrane Geometry. Biophysical Journal. 84, 854-868.
  • Saludjian, P. and Reiss-Husson, F. (1980). Structure of the body-centered cubic phase of lipid systems. Proc. Natl. Acad. Sci. USA. 77(12), 6991-6995.
  • Shah JC, Sadhale Y, and Chilukuri DM. Adv Drug Deliv Rev. 2001 Apr 25;47(2-3):229-50.