WHAT IS A LIPOSOME?
Liposomes are hollow nanospheres made of a double lipidic layer that enclose an aqueous core. They are similar to micelles besides the size and the number of lipidic layers.
Normally, the lipids employed for liposomes are phospholipids like phosphatidylcholine or cholesterol, that are also naturally present in cell membranes. However, other compounds can be used instead, for example, polymers or artificial surfactants (ckeck Polymeric nanoparticles) à Enlace a Polymeric nanoparticles.
Lipids have two differentiated parts. A hydrophilic or water-loving part referred to as the “head” that consists of a negatively charged phosphate group and, attached to it, two parallel uncharged fatty acid chains hang making the hydrophobic or water-hating “tail”. The special structure of the lipids is what gives them the amphiphilic properties that are essential to form emulsions and liposomes. Differences in the head and tail chemical structure, lead to the occurrence of multiple phospholipid varieties.
When they are placed in an aqueous media, the hydrophobic tails arrange together to avoid being in contact with the water, forming simple (micelles) or double (like in liposomes or cell membranes) layers and finally assembling in a spherical shape with the phospholipid heads facing outwards. This process is eased further if energy is applied like with sonication, homogenization, heating or even simply shaking.
WHAT IS A LIPOSOME DELIVERY SYSTEM?
Liposomes are the most well-known nanocarrier. Their properties allow the solubilization, carriage and protection of pharmaceutical drugs to their therapeutic target. Since first described in 1974, they have been used in multiple biomedical areas as pharmaceutical formulation enhancers improving the pharmacokinetics and pharmacodynamics of new therapeutical compounds. Not only have liposomes enabled the use of insoluble pharmaceuticals, but also have allowed the improvement of already in-use formulas.
Mimik natural cell membranes
Liposome composition is very similar to natural cell membranes; they contain phospholipids and cholesterol which reduces immune system triggering and clearance. Additionally, they have very safety profile, with little to no toxicity problems.
Another challenge faced in the pharmaceutical industry is the degradation of the drug compound under light, pH or oxidative conditions. Liposomes help maintaining the therapeutic activity and molecular integrity of the susceptible pharmaceuticals.
Manufacturing methods for liposomes are easily scalable compared to other nanocarrier products.
Hydrophilic and hydrophobic drugs
Liposomes have two possible compartments in which to solubilize compounds, one being within the lipid membrane, for hydrophobic compounds and the other the aqueous core the membrane encloses for hydrophilic compounds. This versatility allows the use of lipophilic drugs without the drawbacks of applying toxic solubilizing agents.
LIPOSOMES VS LIPID NANOPARTICLES VS NIOSOMES
There are many liposome-like carriers that have been used as drug delivery systems. The most well known are solid lipid nanoparticles and niosomes.
SOLID LIPID NANOPARTICLES
Solid lipid nanoparticles or SLNs are another type of lipid based nanocarrier formed as aqueous colloidal dispersions. Unlike liposomes, they have a single lipid layer, and contain a crystalline matrix of solid lipids at room and body temperature. Normally, they are spherical, but other shapes have also been described. Emulsifiers play their part by reducing the interfacial tension (between the solid lipids and the aqueous dispersion media) and thus, stabilizing the SLNs and preventing agglomeration.
There is more flexibility in the use of lipids for solid lipid nanoparticles, including tryglycerides, partial glycerides, fatty acids, fatty esters, fatty alcohols, steroids, and waxes. As with any other nanovehicle, their composition and physicochemical properties will determine its drug loading capacity and its pharmacological behaviour.
SLNs can carry multiple active compounds between the fatty acid chains or attached to its surface (such as drugs, genes, DNA, plasmid, and proteins) and can be used for various application routes (parenteral, oral, dermal, ocular, and pulmonar).
Still, the loading capacity is a strong limitation, especially in the case of low solubility in the lipid mixture. This is where nanostructured lipid carries come into play as an improved second-generation SLNs. The main difference is the use of a combination of liquid oils and solid lipids in its core structure, that increases the drug loading and allows better control over the drug release pace.
Niosomes are another type of nanovesicle used as drug carriers based on non-ionic surfactant bilayer with cholesterol. The most common surfactants include Tween and Span. Similarly, to lipids in liposomes, the surfactant molecules are amphiphilic which allows them to self-assemble in closed bilayers when placed in aqueous media. This is favoured if energy is applied in the form of heat or agitation.
The surfactants in this case, have an uncharged single hydrophobic chain, whereas phospholipids have a neutral or charged double chain. The amount of cholesterol is also lower compared to liposomes which has been shown to improve the loading capacity of the vesicles. In this regard, the components, and physical characteristics of the nanovesicle will determine its properties and in vivo behaviour, as the stability over time and storage temperature.
Their main advantage over liposomes is that niosomes are more stable against oxidation and temperature. The use of non-ionic surfactants allows niosomes to be more permeable through biological membranes while still being innocuous and biodegradable. Additionally, the use of non-ionic surfactants is a more economical alternative since they don’t require an established purity and storage conditions unlike phospholipids. On the other hand, they may be prone to aggregation, which is why proniosomes where developed. Proniosomes are dry preformed niosomes that can be hydrated in an aqueous media to create a fresh niosomal dispersion, thus avoiding stability issues.
Niosomes and proniosomes have been extensively used in the cosmetic industry as skin delivery systems. Well renowned brands as L’Oréal and Lancôme were pioneers in this innovative field introducing niosomes in their products and even patenting ones of their own.
USES AND APPLICATIONS
Gene therapy: The use of genetic material as therapeutic compounds to adjust dysfunctional cell behaviors is a revolutionary approach that has gained more attention in recent years in the medical field. Up or downregulation of genetic expression leads to an increased or decreased production of proteins respectively. The main challenge that gene therapy faces with naked genetic material is the low transfection rates and thus, therapeutic efficacy. Their physical properties as big sizes and polarity, difficult the permeation thought cell and nucleus membranes as well as are susceptible to enzymatic degradation.
Liposomes and other lipid based nanovesicles are able to encapsulate DNA, RNA, siRNA, antisense oligonucleotides, aptamers, DNAzymes, plasmid DNA protecting them along the way until the cell nucleus. The main advantage over the traditional viral vectors is that there are less safety concerns regarding their use. This concept has already been applied to multiple diseases as cystic fibrosis, anemia, immune system deficiencies, viral transmissible diseases, neurological diseases, and hemophilia.
Cancer therapy: The development of highly cytotoxic drugs is needed for the success of the treatment in tumor cells. Paradoxically, the high toxicity limits its efficacy and application in vivo, causing damage to non-target organs and severe secondary effects. The use of directed liposomes has allowed the advance of many cancer drugs to preclinical and clinical trials, reducing side effects, and increasing their therapeutic index at the same time. More than 15 cancer liposomed drugs are currently clinically available.
Ocular drug delivery: The defense mechanisms observed in the eye (epithelium, tear flow and blinking reflex) hamper the drug penetration into deeper layers of the eye. The use of modified liposomes with mucoadhesive polymers and a specific lipid formula helped in overcoming these surface obstacles and reaching target areas as the conjunctival sac.
Brain drug delivery: The trespassing of the blood brain barrier is a challenge for the treatment of central nervous diseases such as Alzheimer, Parkinson, stroke, or cancer (glioma). The endothelium shows tight junctions and specialized transporters which limits the bioavailability of drugs in the central nervous system. The most invasive way of reaching the brain is directly injecting the drug in the brain through a catheter, which has many risks associated. Encapsulation of the drug in liposomes allow a non-invasive way to penetrate this barrier, since they are able to circulate, reach and permeate through it with adequate targeting strategies. Currently this is already being exploited and several liposomed central nervous system pharmaceuticals are in clinical trials or already marketed for the treatment of meningitis, pediatric brain tumors and glioblastoma with great success.
Vaccines: Antigens can be carried by liposomes, either lipids, proteins, DNA or RNA. They can also be combined with bacteria or virus components to form archaeosomes or virosomes, respectively. These vaccines have been proved to be effective in inducing immune responses and providing a sustained exposure to the antigen. More than 30 clinical trials are currently using liposomes for vaccine delivery including HIV and several types of cancer.
Immunomodulating response: The increase or decrease of a natural immune response to obtain a therapeutic result is the basis of immunotherapy. It holds great promise for the treatment of autoimmune diseases, cancer, and the prevention of transplant rejection.
During the onset of autoimmune diseases, the immune system of the host detects an endogenous substance as a threat and becomes a target. For example, β-cell proteins in Type 1 diabetes, myelin peptides in multiple sclerosis, healthy skin cell proteins and lipids in psoriasis and citrullinated proteins in rheumatoid arthritis. Phosphatidyl serine liposomes encapsulating autoantigens have been extensively used for their safe presentation to dendritic cells and stimulate immune self-tolerance. Other approaches include the encapsulation of immunosuppressive drugs or siRNA or oligonucleotides in substitution for the autoantigen.
This tactic can also be translated to the prevention of transplant rejection instead of the administration of immunosuppressives which has many risks associated including infections and cancer. The promotion of self-tolerance has not only been safer but also more successful in the long term for transplant patients.
On the contrary case is cancer, in which the body is inactive towards tumoral cells, and the immune response need to be stimulated. Some strategies include the encapsulation in liposomes of tumor associated antigens (TAAs) or nucleotides encoding for TAAs to activate a CD8+ T-cell response.
Tissue engineering: Tissue regeneration is aimed at the reconstruction of a tissue or organ that requires that cells coordinate timely and spatially to proliferate and differentiate. This comprises complex cell signaling to regulate cellular activity. The delivery of growth and differentiation factors face a rapid in vivo clearance that will benefit greatly from encapsulation in liposomes. Apart from protection, liposomes target the specific cell populations to develop in a scaffold and allow a spatio-temporal controlled delivery. Wound healing is another field in which liposomes have been used with great outlooks, specially for impaired wound healing cases, protecting short life pharmaceuticals, and accelerating neovascularization and epithelialization.
WHAT KIND OF DRUGS MAY BE DELIVERED BY A LIPOSOME?
Proteins and enzymes
HOW DO LIPOSOMES PROVIDE A WAY OF TARGETING DRUGS TO A SPECIFIC TISSUE?
Liposome physico-chemical properties must be tailored to every delivery project to yield the expected therapeutical effects.
Regarding liposome composition, there is a wide range of phospholipids with different features that allow the control of its targeting abilities:
- Fluorescence phospholipids for tracking and imaging applications
- Cationic phospholipids for gene delivery
- Anionic phospholipids like phosphatidylserine for immune system targeting
- PEGylated phospholipids for stealth delivery
- Functionalized head groups for the covalence union of the lipid with targeting compounds such as peptides or antibodies
- pH ionizable phospholipids for mRNA delivery
- Addition of coating compounds for targeting like chitosan, PEI, pectin, or hyaluronic acid
The physical properties such as size and lamellarity are closely related to its pharmacokinetics and drug loading capacity. They depend on the composition but mainly on the production methods, and thus, can be adjusted for each target.
Size and lamellarity are directly proportional to the amount of drug it can encapsulate since they increase the volume of the compartments accommodating both hydrophilic (core) and hydrophobic (membrane) compounds.
BUY LIPOSOMES FOR DRUG DELIVERY
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