Transfersome
Encyclopedia
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.
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.
), 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.
Since it is 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
.
). 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
.
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.
. This ability relies on minimisation of the carrier-associated drug clearance through cutaneous blood vessel
s plexus: the non-fenestrated blood capillary walls in the skin together with the tight junction
s 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.
, extrusion
, low shear rates mixing (multilamellar liposomes), or high high-shear homogenisation unilamellar liposomes) of the crude vesicle suspension.
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
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
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
or a cell engaged in exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
, 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
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
. 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
Drug carrier
Drug carriers are substances that serve as mechanisms to improve the delivery and the effectiveness of drugs. Drug carriers are used in sundry drug delivery systems such as:*controlled-release technology to prolong in vivo drug actions;...
for non-invasive targeted drug delivery
Targeted drug delivery
Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. The goal of a targeted drug delivery system is to prolong, localize, target...
and sustained release
Sustained release
Time release technology, also known as sustained-release , sustained-action , extended-release , time-release or timed-release, controlled-release , modified release , or continuous-release , is a mechanism used in pill tablets or capsules to...
of therapeutic
Therapy
This is a list of types of therapy .* Adventure therapy* Animal-assisted therapy* Aquatic therapy* Aromatherapy* Art and dementia* Art therapy* Authentic Movement* Behavioral therapy* Bibliotherapy* Buteyko Method* Chemotherapy...
agents.
Composition and mechanism of action
The carrier aggregate is composed of at least one amphiphat (such as phosphatidylcholinePhosphatidylcholine
Phosphatidylcholines are a class of phospholipids that incorporate choline as a headgroup.They are a major component of biological membranes and can be easily obtained from a variety of readily available sources such as egg yolk or soy beans from which they are mechanically extracted or chemically...
), which in aqueous solvents self-assembles
Self-assembly
Self-assembly is a term used to describe processes in which a disordered system of pre-existing components forms an organized structure or pattern as a consequence of specific, local interactions among the components themselves, without external direction...
into lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
that closes into a simple lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
. By addition of at least one bilayer softening component (such as a biocompatible surfactant
Surfactant
Surfactants are compounds that lower the surface tension of a liquid, the interfacial tension between two liquids, or that between a liquid and a solid...
or an amphiphile drug) lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
flexibility and permeability
Semipermeable membrane
A semipermeable membrane, also termed a selectively permeable membrane, a partially permeable membrane or a differentially permeable membrane, is a membrane that will allow certain molecules or ions to pass through it by diffusion and occasionally specialized "facilitated diffusion".The rate of...
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
Liposome
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. Liposomes are composite structures made of phospholipids and may contain small amounts of other molecules...
), the Transfersome thus differs from such more conventional vesicle primarily by its "softer", more deformable, and better adjustable artificial membrane
Artificial membrane
An artificial membrane, or synthetic membrane, is a synthetically created membrane which is usually intended for separation purposes in laboratory or in industry. Synthetic membranes have been successfully used for small and large-scale industrial processes since the middle of twentieth century. A...
.
Another beneficial consequence of strong bilayer deformability is the increased Transfersome affinity to bind and retain water. An ultradeformable and highly hydrophilic
Hydrophile
A hydrophile, from the Greek "water" and φιλια "love," is a molecule or other molecular entity that is attracted to, and tends to be dissolved by water. A hydrophilic molecule or portion of a molecule is one that has a tendency to interact with or be dissolved by, water and other polar substances...
vesicle always seeks to avoid dehydration; this may involve a transport process related to but not identical with forward osmosis
Forward osmosis
Forward osmosis is an osmotic process that, like reverse osmosis, uses a semi-permeable membrane to effect separation of water from dissolved solutes...
. For example, a Transfersome vesicle applied on an open biological surface, such as non-occluded skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, 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.
Since it is too large to diffuse
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
through the skin, the Transfersome needs to find and enforce its own route through the organ. The Transfersome vesicles usage in drug delivery
Drug delivery
Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Drug delivery technologies modify drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy and safety, as well...
consequently relies on the carrier’s ability to widen and overcome the hydrophilic
Hydrophile
A hydrophile, from the Greek "water" and φιλια "love," is a molecule or other molecular entity that is attracted to, and tends to be dissolved by water. A hydrophilic molecule or portion of a molecule is one that has a tendency to interact with or be dissolved by, water and other polar substances...
pores in the skin or some other (e.g. plant cuticle
Plant cuticle
Plant cuticles are a protective waxy covering produced only by the epidermal cells of leaves, young shoots and all other aerial plant organs without periderm...
) barrier. The subsequent, gradual agent release from the drug carrier
Drug carrier
Drug carriers are substances that serve as mechanisms to improve the delivery and the effectiveness of drugs. Drug carriers are used in sundry drug delivery systems such as:*controlled-release technology to prolong in vivo drug actions;...
allows the drug molecules to diffuse
Diffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
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
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, unless the vesicle is taken-up actively by the cell in the process called endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
.
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 sigmoidallySigmoid function
Many natural processes, including those of complex system learning curves, exhibit a progression from small beginnings that accelerates and approaches a climax over time. When a detailed description is lacking, a sigmoid function is often used. A sigmoid curve is produced by a mathematical...
). The bulk suspension viscosity governs the highest achievable penetrability; a suspension of ideal Transfersome vesicles, experiencing no friction
Friction
Friction is the force resisting the relative motion of solid surfaces, fluid layers, and/or material elements sliding against each other. There are several types of 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
Active transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
.
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 diffuseDiffusion
Molecular diffusion, often called simply diffusion, is the thermal motion of all particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size of the particles...
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 tissueBiological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
. This ability relies on minimisation of the carrier-associated drug clearance through cutaneous blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s plexus: the non-fenestrated blood capillary walls in the skin together with the tight junction
Tight junction
Tight junctions, or zonula occludens, are the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. It is a type of junctional complex present only in vertebrates...
s between endothelial cells preclude vesicles getting directly into blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, thus maximising local drug retention and propensity to reach the peripheral tissue targets. The Non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
(NSAID) ketoprofen
Ketoprofen
Ketoprofen, 2--propionic acid is one of the propionic acid class of non-steroidal anti-inflammatory drug with analgesic and antipyretic effects...
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 sonicatingSonication
thumb|right|A sonicator at the [[Weizmann Institute of Science]] during sonicationSonication is the act of applying sound energy to agitate particles in a sample, for various purposes. In the laboratory, it is usually applied using an ultrasonic bath or an ultrasonic probe, colloquially known as...
, extrusion
Extrusion
Extrusion is a process used to create objects of a fixed cross-sectional profile. A material is pushed or drawn through a die of the desired cross-section...
, low shear rates mixing (multilamellar liposomes), or high high-shear homogenisation unilamellar liposomes) of the crude vesicle suspension.