Definitions

Transfersome

Transfersome

Transfersome is a term registered as a trademark by the German company IDEA AG, and used by it to refer to its proprietary drug delivery technology. The name means “carrying body”, and is derived from the Latin word 'transferre', meaning ‘to carry across’, and the Greek word ‘soma’, for a ‘body’. A Transfersome carrier is an artificial vesicle designed to be like a cell vesicle or a cell engaged in exocytosis, and thus suitable for controlled and, potentially targeted, drug delivery.

Discovery

The term Transfersome and the underlying concept were introduced in 1991 by Gregor Cevc. Numerous groups have since been working with similar carriers, frequently under different names (elastic vesicle, flexible vesicle, Ethosome, etc.) to describe them.

In broadest sense, a Transfersome is a highly adaptable and stress-responsive, complex aggregate. Its preferred form is an ultradeformable vesicle possessing an aqueous core surrounded by the complex lipid bilayer. Interdependency of local composition and shape of the bilayer makes the vesicle both self-regulating and self-optimising. This enables the Transfersome to cross various transport barriers efficiently, and then act as a Drug carrier for non-invasive targeted drug delivery and sustained release of therapeutic agents.

Composition and mechanism of action

The carrier aggregate is composed of at least one amphiphat (such as phosphatidylcholine), which in aqueous solvents self-assembles into lipid bilayer that closes into a simple lipid vesicle. By addition of at least one bilayer softening component (such as a biocompatible surfactant or an amphiphile drug) [lipid bilayer]] flexibility and permeability are greatly increased. The resulting, flexibility and permeability optimised, Transfersome vesicle can therefore adapt its shape to ambient easily and rapidly, by adjusting local concentration of each bilayer component to the local stress experienced by the bilayer. In its basic organization broadly similar to a liposome), the Transfersome thus differs from such more conventional vesicle primarily by its "softer", more deformable, and better adjustable artificial membrane.

Another beneficial consequence of strong bilayer deformability is the increased Transfersome affinity to bind and retain water. An ultradeformable and highly hydrophilic vesicle always seeks to avoid dehydration; this may involve a transport process related to but not identical with forward osmosis. For example, a Transfersome vesicle applied on an open biological surface, such as non-occluded skin, tends to penetrate its barrier and migrate into the water-rich deeper strata to secure its adequate hydration. Barrier penetration involves reversible bilayer deformation, but must not compromise unacceptably either the vesicle integrity or the barrier properties for the underlying hydration affinity and gradient to remain in place.

Being too large to diffuse through the skin, the Transfersome needs to find and enforce its own route through the organ. The Transfersome vesicles usage in drug delivery consequently relies on the carrier’s ability to widen and overcome the hydrophilic pores in the skin or some other (e.g. plant cuticle) barrier. The subsequent, gradual agent release from the drug carrier allows the drug molecules to diffuse and finally bind to their target. Drug transport to an intra-cellular action site may also involve the carrier’s lipid bilayer fusion with the cell membrane, unless the vesicle is taken-up actively by the cell in the process called endocytosis.

Characterisation

The mechanical properties and transport ability of a vesicle can be studied by measuring stress- or deformation-dependent vesicle bilayer elasticity and permeability changes. In a single experiment the objective may be reached by determining the pressure dependent area density of the Transfersome suspension flux through a nano-porous filter, with pores at least 50% smaller than the average vesicle size. For the proper Transfersome vesicles, the experiment derived proportionality function, so-called “Penetrability”, increases non-linearly with the flux driving force (head pressure), often sigmoidally). The bulk suspension viscosity governs the highest achievable penetrability; a suspension of ideal Transfersome vesicles, experiencing no friction in the barrier, therefore yields similar maximum penetrability value as the comparably tested vesicles-suspending fluid. On the other hand, the characteristic pressure needed to enforce a significant transport rate with the vesicles suspension mainly depends on the explored bilayer adaptability. Analysis of experimental Penetrability vs. Driving pressure curves can therefore yield the characteristic bilayer elasticity and permeability values, based on theoretical description of material flow as an activated transport process.

Usage

Transfersome technology is best suited for non-invasive delivery of therapeutic molecules across open biological barriers. The Transfersome vesicles can transport across the skin, for example, molecules that are too big to diffuse through the barrier. Examples include systemic delivery of therapeutically meaningful amounts of macromolecules, such as insulin or interferon, across intact mammalian skin. Other applications include the transport of small molecule drugs which have certain physicochemical properties which would otherwise prevent them from diffusing across the barrier.

Peripheral tissue targeting

Another attraction of the Transfersome technology is the carriers ability to target peripheral, subcutaneous tissue. This ability relies on minimisation of the carrier-associated drug clearance through cutaneous blood vessels plexus: the non-fenestrated blood capillary walls in the skin together with the tight junctions between endothelial cells preclude vesicles getting directly into blood, thus maximising local drug retention and propensity to reach the peripheral tissue targets. The Non-steroidal anti-inflammatory drug (NSAID) ketoprofen in a Transfersome formulation gained marketing approval by the Swiss regulatory agency (SwissMedic) in 2007; the product is expected to be marketed under the trademark Diractin. Further therapeutic products based on the Transfersome technology, according to IDEA AG, are in clinical development.

Manufacturing

Transfersome vesicles are prepared in a similar manner as liposomes, except that no separation of the vesicle-associated and free drug is required. Examples include sonicating , extrusion, low shear rates mixing (multilamellar liposomes), or high high-shear homogenisation unilamellar liposomes) of the crude vesicle suspension.

References

  • G. Gompper, D.M. Kroll "Driven transport of fluid vesicles through narrow pores". Physical Review E 52 (4): 4198–4208.
  • G. Cevc, A. Schätzlein, H. Richardsen "Ultradeformable Lipid Vesicles can Penetrate the Skin and other Semi-Permeable Barriers Intact. Evidence from Double Label CLSM Experiments and Direct Size Measurements". Biochim. Biophys. Acta 1564 21–30.
  • G. Cevc, A. Schätzlein, H. Richardsen, U. Vierl "Overcoming semi-permeable barriers, such as the skin, with ultradeformable mixed lipid vesicles, Transfersomes, liposomes or mixed lipid micelles". Langmuir 19 (26): 10753–10763.
  • G. Cevc, D. Gebauer "Hydration-driven transport of deformable lipid vesicles through fine pores and the skin barrier.". Biophysical Journal 84 (4): 1010–1024.
  • G. Cevc "Lipid vesicles and other colloids as drug carriers on the skin". Advanced Drug Delivery Reviews 56 (5): 675–711.

Further reading

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