- Liposome as a Carrier for Advanced Drug Delivery
- 1. Introduction
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In these measurements, the signal due to intact liposomes is typically monitored prior to bilayer disruption. The techniques used for this quantification depend on the nature of the encapsulant and include spectrophotometry [ , ], fluorescence spectroscopy [ ], enzyme-based methods [ ] and electrochemical techniques. If a separation technique such as HPLC of field-flow fractionation FFF is applied, the percent encapsulation can be expressed as the ratio of the unencapsulated peak area to that of a reference standard of the same initial concentration [ , ].
This method can be applied if the liposomes do not undergo any purification following preparation. Either technique serves to separate liposome encapsulated materials from those that remain in the extravesicular solution and hence can also be used to monitor the storage stability in terms of leakage or the effect of various disruptive conditions o the retention of encapsulants. Some authors have combined the size distribution and encapsulation efficiency determination in one assay by using FFF-MALS multi angled light scattering coupled to a concentration detector suitable for the encapsulant [ ].
Since techniques used to separate free materials from liposome-encapsulated contents can potentially cause leakage of contents and, in some cases, ambiguity in the extent of separation, research using methods that do not rely on separation are of interest. Reported methods have included 1H NMR where free markers exhibited pH sensitive resonance shifts in the external medium versus encapsulated markers [ ]; diffusion ordered 2D NMR which relied on differences in diffusion coefficients of entrapped and free marker molecules [ ]; fluorescence methods where the signal from unencapsulated fluorophores was quenched by substances present in the external solution [ ]; electron pin resonance ESR methods which rely on the signal broadening of unencapsulated markers by the addition of a membrane-impermeable agent [ , ].
The drug release from liposomes can be followed by the usage of a well calibrated in vitro diffusion cell in order to predict pharmacokinetics and bioavailability of drug before expensive and time-consuming in vivo studies. For the determination of pharmacokinetic performance of liposomal formulations, dilution-induced drug release in buffer and plasma was employed and for the determination of drug bioavailability, another procedure is followed which involves the liposome degradation in the presence of mouse-liver lysosome lysate [ 93 ]. New drug delivery systems such as liposomes are developed when the existing formulations are not satisfactory.
Among all the nanomedicine platforms, liposomes have demonstrated one of the most established nanoplatforms with several FDA-approved formulations for cancer treatment, and had the greatest impact on oncology to date, because of their size, biocompatibility, biodegradability, hydrophobic and hydrophilic character, low toxicity and immunogenicity [ ]. Liposome applications in drug delivery depend, and are based on, physicochemical and colloidal characteristics such as composition, size, loading efficiency and the stability of the carrier, as well as their biological interactions between liposomes and cells.
Based on these liposome properties, several modes of drug delivery can be listed: the major ones are enhanced drug solubilization e. Although lipid based formulations have advantages as drug carriers, drug-delivery systems based on unmodified liposomes are limited by their short blood circulation time, instability in vivo and lack of target selectivity [ , ]. To increase accumulation of liposomal formulations in the desired cells and tissues, the use of targeted liposomes including surface-attached ligands such as; antibodies, folates, peptides and transferrin that are capable of recognizing and binding to the desired cells.
Despite of some improvements in targeting efficiency by these immunoliposomes, the majority of these modified liposomes were still eliminated rapidly by the reticulo endothelial system, primarily in the liver [ ]. Better target accumulations are expected if liposomes can be made to remain in the circulation long enough.
Schematic drawing of cytosolic delivery and organelle-specific targeting of drug loaded nanoparticles i. Schematic drawing of the cytosolic delivery and organelle-specific targeting of drug loaded nanoparticles via receptor-mediated endocytosis.
Liposome as a Carrier for Advanced Drug Delivery
After receptor mediated cell association with nanoparticles, the nanoparticles are engulfed in a vesicle known as an early endosome. Nanoparticles formulated with an endosome disrupting property disrupt the endosomes followed by cytoplasmic delivery. On the other hand, if nanoparticles are captured in early endosomes, theymaymake theirway to lysosomes as late endosomes where their degradation takes place. Only fraction of non-degraded drug released in the cytoplasm interacts with cellular organelles in a random fashion. However, cytosolic delivery of a fraction of organelle-targeted nanoparticles via endosomal escape or from lysosomes travel to the targeting organelles to deliver their therapeutic cargo .
Different methods have been suggested to achieve liposomes with high stability and long circulation times in vivo, including the surface coating of the liposomes with inert, biocompatible polymers such as PEG stealth liposomes , which forms a protective layer over the liposome surface and slow down liposome recognition by opsonins and therefore subsequent clearance of liposomes [ 80 , 84 ]. Long circulating liposomes are now being investigated in detail and are widely used in vitro and in vivo studies due their flexibility and also they found their place in the clinical applications.
The flexibility allows a relatively small number of surface-grafted polymer molecules to create an impermeable layer over the liposome surface [ , ]. Long-circulating liposomes demonstrate dose-dependent, non-saturable, log-linear kinetics and increased bioavailability [ ]. The studies that attempt to combine the properties of long-circulating liposomes and immunoliposomes in one preparation place themselves in the literature as the further development in the liposomal formulations as drug carriers [ , ].
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In the early experiments, simple co-immobilization of an antibody and PEG on the surface of the same liposome has been performed despite the possibility of PEG creating steric hindrance for target recognition with the targeting moiety [ ]. To achieve better selectivity of PEG-coated liposomes, it is advantageous to attach the targeting ligand via a PEG spacer arm, so that the ligand is extended outside the dense PEG brush which reduces steric hindrance of binding to the target [ ]. The use of PEG-conjugated immunoliposomes for increasing drug carrying capacity of monoclonal antibody has been demonstrated [ ].
In addition to costly monoclonal antibodies, common molecules such as folic acid, trensferrin and RGD peptides have also been studied for tumor targeting with enhanced selective uptakes [ ]. Encouraging results of liposomal drugs in the treatment or prevention of a wide spectrum of diseases in experimental animals and in human, indicate that more liposome-based products for clinical and veterinary applications may be forthcoming.
These could include treatment of eye and skin diseases in therapeutic applications, antimicrobial and anticancer therapy in clinical applications, metal chelation, enzyme and hormone replacement therapy, vaccine and diagnostic imaging, etc.
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Some of the liposome applications in terms of drug delivery are discussed below. The eye is protected by three highly efficient mechanisms a an epithelial layer which is the barrier to penetration b tear flow c the blinking reflex. All these mechanisms are responsible for the poor drug penetration into the deeper layers of the cornea and the aqueous humor and for the rapid wash out of drugs from the corneal surface. Initially, in the enhanced efficiency of liposomes encapsulated idoxuridine in herpes simplex infected corneal lesions in rabbits was reported [ ].
In , it was concluded that ocular delivery of drugs can be either promoted or impeded by the use of liposome carriers, depending on the physicochemical properties of the drugs and the lipid mixture employed [ ]. The use of mucoadhesive polymers, carbopol P and carbopol to retain liposomes at the cornea was proposed [ ]. While precorneal retention times were indeed significantly enhanced under appropriate conditions, liposomes even in the presence of the mucoadhesive had migrated toward the conjuctival sac with very little activity remaining at the corneal surface.
Lung is a natural target for the delivery of therapeutic and prophylactic agents such as peptides and proteins. The past 15 years have been marked by intensive research efforts on pulmonary drug delivery not only for local therapy but also for systemic therapy as well as diagnostic purposes, primarily due to the several advantages the pulmonary route offers over other routes of drug administration. Drugs that undergo gastrointestinal degradation such as proteins and peptides are ideal candidates for pulmonary delivery. Targeted drug delivery to the lungs has evolved to be one of the most widely investigated systemic or local drug delivery approaches.
The use of drug delivery systems for the treatment of pulmonary diseases is increasing because of their potential for localized topical therapy in the lungs. This route also makes it possible to deposit drugs more site-specific at high concentrations within the diseased lung thereby reducing the overall amount of drug activity while reducing systemic side effects.
To further exploit the other advantages presented by the lungs, as well as to overcome some challenges, scientists developed interests in particulate drug delivery systems for pulmonary administration, such as liposomes, micelles, nano-and micro-particles based on polymers. The use of liposomes as drug carriers for pulmonary delivery has been reported for different kinds of therapeutics such as anti-microbial agents, cytotoxic drugs, antioxidants, anti-asthma compounds and recombinant genes for gene therapy in the treatment of cystic fibrosis.
Liposomes as carrier systems for pulmonary delivery offer several advantages over aerosol delivery of the corresponding non-encapsulated drug. Local delivery of medication to the lungs is highly desirable, especially in patients with specific pulmonary diseases such as cystic fibrosis, asthma, chronic pulmonary infections or lung cancer. The principal advantages include reduction of systemic side effects and application of higher doses of the medication at the site of drug action. Although simple inhalation devices and aerosols containing various drugs have been used since the early 19th century for the treatment of respiratory disorders, the past 15 years have been marked by intensive research efforts on pulmonary drug delivery not only for local therapy but also for systemic therapy as well as diagnostic purposes due to the several advantages the pulmonary route offers over other routes of drug administration.
Lung is a natural target for the delivery of therapeutic and prophylactic agents such as peptides and proteins due to the large surface area available for absorption, the very thin absorption membrane and the elevated blood flow which rapidly distributes molecules throughout the body. Moreover, the lungs exhibit relatively low local metabolic activity, and unlike the oral route of drug administration, pulmonary inhalation is not subject to first pass metabolism [ ]. Inhaled drug delivery devices can be divided into three principal categories: nebulizers, pressurized metered-dose inhalers and dry powder inhalers; each class presents unique strengths and weaknesses.
A good delivery device has to generate an aerosol of suitable size and provide reproducible drug dosing. It must also protect the physical and chemical stability of the drug formulation. For controlled delivery of drug to the lung, liposomes are one of the most extensively investigated systems in recent studies given that they can be prepared with phospholipids such as egg phosphatidylcholine PC , distearoyl phosphatidylcholine DSPC and dipalmitoylphosphatidylcholine DPPC endogenous to the lung.
A significant disadvantage of many existing inhaled drugs is the relatively short duration of resultant clinical effects, which requires most medications to be inhaled at least twice daily. This often leads to poor patient compliance. A reduction in the frequency of dosing would be convenient, particularly for chronic diseases such as asthma. The advantages of such an approach include reduced dosing, increased effectiveness of rapidly cleared medicine and enhanced residence time at the target site for the treatment of infection.
Many challenges exist in developing controlled release inhalation medicine, which is reflected in the fact that no commercial product exists. Cytotoxic agents, bronchodilators, anti-asthma drugs, antimicrobial and antiviral agents and drugs for systemic action, such as insulin and proteins are being investigated. The numerous anti-cancer agents that have a high cytotoxic effect on the tumor cells in vitro exhibit a remarkable decrease of the selective ant-tumor effect for in vivo procedures applicable in the clinical treatment.
One of the significant limitations of the anti-cancer drugs is their low therapeutic index meaning that the dose required to produce an anti-tumor effect is toxic to normal tissues. The low therapeutic index of these drugs results from the inability to achieve therapeutic concentrations at the specific target sites, tumors. Further, it results from the non-specific toxicity to normal tissues such as bone marrow, renal, gastrointestinal tract, and cardiac tissue and also from the problems associated with a preparation of a suitable formulation of the drugs [ ].
Many different liposome formulations of various anticancer agents were shown to be less toxic than the free drug so that most of the medical applications of liposomes that have reached the preclinical stage are in cancer treatment [ - ]. Entrapment of these drugs into liposomes resulted in increased circulation lifetime, enhanced deposition in the infected tissues, and protection from the drug metabolic degradation, altered tissue distribution of the drug, with its enhanced uptake in organs rich in mononuclear phagocytic cells liver, spleen and bone marrow and decreased uptake in the kidney, myocardium and brain.
To target tumors, liposomes must be capable of leaving the blood and accessing the tumor. However, because of their size liposomes cannot normally undergo transcapillary passage. In spite of this, various studies have demonstrated the accumulation of liposomes in certain tumors in a higher concentration than found in normal tissues [ , ]. Anthracyclines are drugs which stop the growth of dividing cells by intercalating into the DNA and therefore kill predominantly quickly dividing cells.
These cells are not only in tumors but are also in hair, gastrointestinal mucosa, and blood cells; therefore, this class of drugs is very toxic. Many research efforts have been directed towards improving the safety profile of the anthracyclines cytotoxics, doxorubicin and daunorubicin, along with vincristine. Encapsulation of these drugs into the liposomes showed reduced cardiotoxicity, dermal toxicity and better survival of the experimental animals compared to the controls receiving free drugs [ ].
Such beneficial effects of liposomal anthracyclines have been observed with a variety of liposome formulations regardless of their lipid composition and provided that lipids used high cholesterol concentration of phospholipids with high phase transition temperature are conducive to drug retention by the vesicles in the systemic circulation [ 45 ].
Active targeting of cancer drugs to the tumors is shown schematically in Figure 4. Several other liposomal chemotherapeutic drugs containing doxorubicin, annamycin, mitoxantrone, cisplatin, oxaliplatin, camptothecine, 9-nitro S -camptothecin, irinotecan, lurtotecan, topotecan, paclitaxel, vincristine, vinorelbine and floxuridine are at the various stages of clinical trials [ ].
Doxil, first liposomal drug approved by FDA and has been on the market since , is a formulation of doxorubicin precipitated in sterically stabilized liposomes and has been on the market since [ ], while DaunoXome, approved six months later than Doxil, is daunorubicin encapsulated in small liposomes with very strong and cohesive bilayers, which can be referred as mechanical stabilization [ ].
DaunoXome is composed of small unilamellar vesicles containing distearoylphosphatidylcholine-cholesterol with daunorubicin loaded by a pH gradient [ ]. These liposomes are selectively stable in the circulation because they are small and their membrane is electrically neutral and mechanically very strong [ ]. This reduces the charge-induced and hydrophobic binding of plasma components but does not protect against van der Waals adsorption. Also, uncharged liposomes are colloidally less stable than charged ones. Doxil is a liquid suspension of nm liposomes PEG-distearoylphosphatidylethanolamine-hydrogenated-soya-bean phosphatidylcholine-cholesterol, 20 mM loaded with doxorubicin HCl by ammonium sulfate gradient technique and additionally precipitation with encapsulated sulfate anions.
These liposomes circulate in patients for several days, which increase their chances of extravasating at sites with a leaky vascular system. Their stability is due to their surface PEG coating as well as to their mechanically very stable bilayers [ , ]. Cytarabine Ara-C is an effective hydrophilic chemotherapeutic agent used widely for the treatment of acute myelogenous leukaemia and lymphocytic leukeamia [ ]. It has often been utilized in the combination chemotherapy, against solid tumors and leukaemias.
Cytarabine is a cell cycle-dependent drug; hence, prolonged exposure of cells to cytotoxic concentrations is critical to achieve maximum cytotoxic activity. The toxicity of cytarabine is reduced if it is able to maintain an effective therapeutic level for a long period of time and, thus, it is a suitable candidate for administration in a controlled-release dosage form. Liposome encapsulated liposomes DepoCytTM are now commercially available.
Etoposide VP is another successful chemotherapeutic agents used for the treatment of human cancers. The drug is currently in its third decade of clinical use and is a front line therapy for a variety of malignancies, including leukaemias, lymphomas and several solid tumors [ ]. It has a short biological half-life 3. Although intraperitoneal injection would result in initial high local tumor concentrations, prolonged exposure of tumor cells may not be possible [ ].
The harmful and even destructive effect of cytotoxic drugs on healthy body cells makes it necessary to search for new delivery methods for drugs like cytarabine and etoposide. There are many articles describing the results of investigations of incorporation of cytarabine [ ] and etoposide [ ] into liposome.
However, there is no information about their simultaneous incorporation, in spite of the fact that these two drugs have been used for more than 30 years. Taxanes are complexes of diterpenoid natural products and semisynthetic analogs. Presently, these drugs belong to prominent anticancer agents used for combined chemotherapy [ ].
Paclitaxel PTX , the prototype of this class, emerges from a natural source [ ]. This drug have been used for various cancers including ovarian, breast, head and neck, and non-small cell lung cancers [ ]. However, some drawbacks have been reported for its clinical applications of this formulation such as severe hypersensitivity reactions, neurotoxicity and neutropenia [ , ].
It was reported that these adverse effects associated with this formlation would be due to Cremophor EL rather than PTX itself [ ]. PTX solubilized in Cremophor EL shows also an incompatibility with the polyvinyl chloride of the administration sets [ ]. Furthermore, the short-term stability of PTX upon dilution with aqueous media can result in possible drug precipitation [ ]. Hence, the development of an improved delivery system for PTX is of high importance. Current approaches are focused mainly on the development of formulations that are devoid of Cremophor EL, investigation of the possibility of a large-scale preparation and a request for a longer-term stability.
The preparation of an optimal PTX formulation requires important considerations such as the optimization of the liposomal composition, the balance of the PTX amount encapsulated in the liposomes and the stability of the prepared PTX liposomes during storage in aqueous media [ ]. The main characteristics of PTX molecule are asymmetry, bulkiness, hydrophobicity, low solubility and tendency to crystallization in aqueous media.
All these factors affect the final design and preparation of a suitable drug formulation. Liposomes provide suitable environment enhancing the solubility of the hydrophobic nature PTX by associating the molecule within the membrane bilayers. Generally, increasing the encapsulated amount of PTX causes a reduction in the stability of the liposomal-PTX formulation due to the crystallization of the drug molecule. The encapsulation of PTX into liposomes enhances the drug therapeutic efficacy, thus, the same therapeutic effect could be reached by a decreased PTX-dose.
They have also shown antitumor effect in Taxol-resistant tumor models [ ]. Generally, liposomes and protein nanoparticles represent a promising approach to the optimization of PTX delivery. Their commercialization is at the doorstep of modern drug delivery market. Liposomes made up of commonly used ester phospholipids such as phosphatidylcholine are referred as conventional liposomes. These structures are very attractive for encapsulation and drug delivery applications to entrap both hydrophilic and hydrophobic materials due to the presence of aqueous core part as well as the lipid bilayer.
Up to this date, there are many formulations in the market and also in the clinical trials. However, none of them truly overcome their chemical and physical instability problems especially during the transfer to the site of action [ ]. Various attempts like modification of the liposome surface with i.
Other than instability problems, liposomal drug vehicles show extensive leakage of water-soluble drugs during the passage through the gastrointestinal tract and they are heterogeneous in terms of size distribution. Therefore, scientists have been looking for new drug delivery formulations that could address these issues about liposomes, which lead to the so-called new generation of liposomes which will be summarized in this section. These archaeobacterial lipids present unique features and higher stabilities to several conditions high or low temperatures, high salinity, acidic media, anaerobic atmosphere, high pressure over conventional liposomes [ ].
The definition of archaeosomes also includes the use of synthetically derived lipids that have the properties of archaeobacterial ether lipids, that is, regularly branched phytanyl chains attached via ether bonds at sn-2,3 glycerol carbons [ ]. Archaeosomes can be prepared by using conventional procedures hydration of a thin film followed by sonication or extrusion, detergent dialysis at any temperature in the physiological range or lower, thus making it possible to encapsulate thermally labile compounds.
Additionally, they can be prepared and stored in the presence oxygen without any degradation. According to the clinical experiments, in vivo and in vitro, these new drug delivery vehicles are not toxic. Consequently, they can be considered as better carriers than conventional liposomes, especially for protein and peptide delivery due to their high stability.
Li et al. Another development aiming to enhance tissue targeting is virosomes in which the liposome surface is modified with fusogenic viral envelope proteins [ ]. Virosomes have been used for the intracellular delivery of drugs and DNA [ , ] as well as the basis of the newly developed vaccines which are very effective in the delivery of protein antigens to the immune system [ ]. As a result, a whole set of virosomes-based vaccines have been developed for human and animal use. Special attention has been paid to the delivery of influenza vaccine using virosomes containing the spike proteins of influenza virus.
Virosome-based vaccines were found to be highly immunogenic and well tolerated in children. A similar approach was used to prepare virosomal hepatitis A vaccine that elicited high antibody titres after primary and booster vaccination of infants and young children which was also confirmed for the healthy adults and elderly patients [ - ]. In general, virosomes can provide an excellent opportunity for the efficient delivery of both various antigens and many drugs, including nucleic acids, cytotoxic drugs and toxoids [ , ], although they might present certain problems associated with their stability, leakiness and immunogenicity.
Niosomes, exhibiting a similar behavior to liposomes, are the vesicles that are made up of nonionic surfactants e. These structures are stable on their own and they increase the stability of the encapsulated drugs. No special conditions are needed for handling and storage of these surfactants.
Niosomes improve the oral bioavailability of poorly absorbed drugs, and enhance skin penetration of drug. When compared with liposomes, their oral absorption is better due to the replacement of phospholipids with nonionic surfactants which are less susceptible to the action of bile salts, parenteral, as well as topical routes. These delivery systems are biodegradable, biocompatible and non-immunogenic.
Niosomes improve the therapeutic performance of drug molecules by delaying the clearance from the circulation and protecting the drug from biological environment [ ]. The transdermal delivery is one of the most important routes of drug administration. The main factor which limits the application of transdermal route for drug delivery is the permeation of drugs through the skin.
Human skin has selective permeability for drugs. Lipophilic drugs can pass through the skin but the drugs which are hydrophilic in nature can not pass through. Water soluble drugs either show less or no permeation. To improve the permeation of drugs through the skin various mechanisms have been investigated, including use of chemical or physical enhancers, such as iontophoresis, sonophoresis, etc. Liposomes and niosomes are not suitable for transdermal delivery due to poor skin permeability, breaking of the system, aggregation, drug leakage, and fusion of vesicles [ ].
A new type of carrier system, suitable for transdermal delivery, called transfersome has been proposed for the delivery of proteins and peptides like insulin, bovin, serum albumin, vaccines, etc. Transfersomes improve the site specificity while providing the safety of the drug.
Transfersomes are the lipid supramolecular aggregates which make them very flexible. This flexibility as well as their good penetration ability causes them to be used in the effective delivery of non-steroidal anti-inflammatory agents like ibuprofen and diclofenac [ ]. Alternatively, unlike classic liposomes [ , ], that are known mainly to deliver drugs to the outer layers of skin, ethosomes can enhance permeation through the stratum corneum barrier [ - ].
Ethosomes, developed by Touitou in , are the slight modification of well established drug carrier liposome, containing phospholipids, alcohol ethanol or isopropyl alcohol in relatively high concentration and water [ ]. The size of these soft vesicles can vary from nanometers to microns [ - ].
The high concentration of ethanol makes the ethosomes unique. Also, because of the high concentration of ethanol the lipid membrane is packed less tightly than conventional vesicles but has equivalent stability, allowing a more malleable structure and improves drug distribution ability in stratum corneum lipids.
Novasomes are the modified forms of liposomes [ ] or a type of niosomes prepared from the mixture of monoester of polyoxyethylene fatty acids, cholesterol and free fatty acids with the diameter of 0. They consist of two to seven bilayer shells that surround an unstructured space occupied by a large amorphous core of hydrophilic or hydrophobic materials [ ]. Novasomes offer several advantages to the owners of the product such as: Both hydrophilic and hydrophobic products can be incorporated in the same formulation, drugs showing interactions can be incorporated in between bilayers to prevent incompatibility, they can be made site specific due to their surface charge characteristics, they can deliver a large volume of active ingredient, thus also reducing the frequency of application, and they have the ability of adhering skin or hair shafts which makes novasomes applicable in the cosmetic formulations [ ].
Novasomes have extensive utilization in fields of foods, cosmetics, personal care, chemical, agrochemical and pharmaceuticals. The technology enhances absorption rate via topical delivery of pharmaceuticals and cosmeceuticals by utilizing non-phospholipid structures. Various FDA-regulated products such as human pharmaceuticals and vaccines can be developed by this technology [ , ].
These nonionic vesicles composed of glyceryl dilaurate with cholesterol and polyoxyethylenestearyl ether have been known to deliver greater amounts of cyclosporine into and through hairless mouse skin than phosphatidyl choline or ceramide based vesicles [ ]. Among various liposomal formulations, novasomes appeared more effective when delivered under non-occluded conditions from a finite dose [ ]. Various vaccines based on novasomes have been licensed for the immunization of fowl against Newcastle disease virus and avian rheovirus [ ].
Some of the novasome-based vaccines against bacterial and viral infections have been developed such as small pox vaccine while still many are under development [ ]. Novasomes inactivate viruses such as orthomyxoviruses, paramyxoviruses, coronaviruses and retroviruses, etc. Although liposomes are like biomembranes, they are still foreign objects of the body. Therefore, liposomes are known by the mononuclear phagocytic system MPS after contact with plasma proteins.
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Accordingly, liposomes are cleared from the blood stream. For more than two decades, various PEG derivatives have been used to stabilize for increasing efficiency in drug or gene delivery. Unlike, conventional liposomes, PEG-liposomes do not show dose dependent blood clearance kinetics [ ]. Vesicles containing PEG-conjugated lipids at various concentrations, molecular weights, or various sizes of PEG-containing vesicles were reported to have different circulation times [ 81 , 84 , - ].
These kind of liposomal systems are generally used in the ligand-mediated drug targeting [ ]. This stealth principle has been used to develop the successful doxorubicin-loaded liposome product that is presently available in the market as Doxil Janssen Biotech, Inc. Cryptosomes is a liposomal composition for targeted delivery of drugs. The composition comprises poloxamer molecules and liposomes encapsulating one or more delivery agents. Poloxamers are polyethylene oxide PEO -polypropylene oxide PPO -polyethylene oxide tri-block co-polymers of different molecular weights.
The hydrophilic PEO groups of a poloxamer, on either side of the central PPO unit, can provide steric protection to a bilayer surface. The amphiphilic nature of the poloxamers makes them extremely useful in various applications as emulsifiers and stabilizers. It is considered that the central PPO unit, being hydrophobic, would tend to push into the bilayer interior serving as an anchor.
Dislodging the poloxamer molecule from the bilayer is achieved by reducing its hydrophobicity which is achieved by decreasing the temperature. In an aqueous medium, poloxamers stay as individual molecules at temperatures below their critical micelle temperature CMT , but at temperatures above the CMT, they form micelles due to their amphiphilic nature. In the presence of lipid bilayers, some poloxamer molecules would partition into the bilayers as well as forming micelles with other poloxamer units.
If the temperature again goes below the CMT, the poloxamer molecules lose their amphiphilic nature and disassociate from the lipid bilayer or micelle [ ]. Emulsome, having the characteristics of both liposomes and emulsions, is a novel lipoidal vesicular system with an internal solid fat core surrounded by phospholipid bilayer. Emulsomes comprise a hydrophobic core composed of solid fates instead of oils as in standard oil-in-water emulsions, but the core is surrounded and stabilized by one or more envelopes of phospholipid bilayers as in liposomes allowing water insoluble drugs in the solution form without requiring any surface active agent or co-solvent.
Emulsomes differ from liposomes since their internal core is a lipid, whereas the internal core in liposomes is an aqueous compartment. The drug loading is generally followed by sonication to produce emulsomes of smaller size [ ]. These systems are often prepared by melt expression or emulsion solvent diffusive extraction. Emulsomes provide the advantages of improved hydrophobic drug loading in the internal solid lipid core and the ability of encapsulating water-soluble medicaments in the aqueous compartments of surrounding phospholipid layers.
Beside the other vesicular formulations, emulsomes are much stabilized and nano range vesicles. It is a new emerging delivery system and therefore could play a fundamental function in the effective treatment of life-threatening viral infections and fungal infections such as hepatitis, HIV, Epstein-Barr virus, leishmaniasis, etc.
Emulsomes could be utilized in order to improve oral controlled delivery of drug, vaccine, and biomacromolecules. It is due to the fact that they are nano sized in range and could be utilized for the intravenous route. The common application areas of emulsomes are drug targeting, anti-neoplastic treatment, leishmaniasis a disease in which a parasite of the genus Leishmania invades the cells of the liver and spleen treatment, and biotechnology. Moreover, emulsomes could represent a more economical alternative to current commercial lipid formulations for the treatment of viral infections and fungal infections.
Emulsomes provide a controlled and sustain release of drug. In comparison to the liposomes, emulsomes provide a prolong release of drug up to 24 hours, whereas liposomes have shown release up to 6 hours [ - ]. Emulsomes are nano size range in comparison to other vesicular delivery system such as niosomes and ethosomes. Due to the reduced size nm they can be used to enhance bioavailability to drug and as the best carrier for the intravenous drug delivery as well as oral drug delivery.
The presence of anti-oxidants reduces the formation of oxidative degradation products of unsaturated lipids such as peroxides. The need of anti-oxidant can be prevented by the usage of saturated fatty acids during the preparation of the lipid core [ ]. In the formation of emulsomes, like in the case of liposomes, cholesterol is essential component for the system that influences the stability of emulsomal systems and plays an important role in the drug encapsulation [ - ]. The most important advantage of emulsomes is their ability to protect the encapsulated drug from harsh gastric environment of stomach before oral administration because the drug is inside the triglyceride lipid core which can be supported that the gastric pH and the gastric enzymes are unable to hydrolyze triglycerides.
Also, they resist development of multi drug resistance, often associated with over expression of a cell membrane glycoprotein, which cause efflux of the drug from the cytoplasm and results in an ineffective drug concentration inside the cellular compartment [ ]. The development of emulsomes, however, is still largely empirical, and in vitro models that are predictive of oral bioavailability enhancement are lacking.
There is a need for in vitro methods for predicting the dynamic changes involving the drug in the gut in order to monitor the solubilization state of the drug in vivo. Attention also needs to be paid to the interactions between lipid systems and the pharmacologically active substance.
The characteristics of various lipid formulations also need to be understood, so that guidelines can be established that allow identification of suitable candidate formulations at an early stage. Future research should involve human bioavailability studies as well as more basic studies on the mechanisms of action of this fascinating and diverse group of formulations.
Unilamellar vesicles or liposomes are commonly used as simple cell models and as drug delivery vehicles to follow the release kinetics of lipophilic drugs that require compartmental models in its therapeutics and triggers. The localization of the drug at the site of action, rate of achieving the therapeutic index and circulation lifetime are the key parameters for a liposome. Lately, their arises a need for a multi-compartment structure consisting of drug-loaded liposomes encapsulated within another bilayer, is a promising drug carrier with better retention and stability due to prevention enzymes or proteins reaching the interior bilayers.
A vesosome is a more or less heterogeneous, aggregated, large lipid bilayer enclosing multiple, smaller liposomes that offer a second barrier of protection for interior compartments and can also serve as the anchor for active targeting components [ , 76 ]. The multi-compartment structure of vesosome can also allow for independent optimization of the interior compartments and exterior bilayer; however, just the bilayer-within-a-bilayer structure of the vesosome is sufficient to increase drug retention from minutes to hours [ , ].
In nature, eukaryotes increased their ability to optimize their response to their surroundings by developing multiple compartments, each of which has a distinct bilayer membrane, usually of quite varied composition and physical structure. Mimicking this natural progression to nested bilayer compartments led to the development of the vesosome, or vesicles deliberately trapped within another vesicle. The vesosome has distinct inner compartments separated from the external membrane; each compartment can encapsulate different materials and have different bilayer compositions. In addition, while it has proven difficult to encapsulate anything larger than molecular solutions within lipid bilayers by conventional vesicle self-assembly, the vesosome construction process lends itself to trapping colloidal particles and biological macromolecules relatively efficiently [ , ].
The nested bilayer compartments of the vesosome provide a degree of freedom for optimization not possible with a single membrane enclosed compartment and a more realistic approximation of higher order biological organization. The vesosome structure could be used to deliver a cocktail of antibiotics or antimicrobials to sites at a fixed ratio; such mixtures have been shown to act synergistically when delivered in a single liposome [ ].
Such multi-drug formulations may be useful to avoid inducing pathogen resistance to a single drug. As vesosomes are simply liposomes within liposomes, it should be possible to directly translate the extensive body of research on liposome drug delivery to the vesosome with only minor changes, and perhaps significant major improvements. The vesosome is created by simply self-assembly steps very similar to those used in making conventional unilamellar liposomes [ ].
An important question is whether such additional effort in developing new structures will provide a therapeutic benefit over direct injection of the free drug or drug delivery by conventional unilamellar liposomes. The most obvious potential application for the vesosome is for drugs that have already shown increased efficacy by delivery with conventional liposomes.
As an example, ciprofloxacin cipro , a synthetic bactericidal fluoroquinolone antibiotic with broad spectrum efficacy, is released much more quickly from unilamellar liposomes in serum relative to saline [ , ]. Conventional pH-loaded liposomes can retain essentially all encapsulated ciprofloxacin when stored in buffer for 12 weeks at 21 0C and 8 weeks at 37 0C [ , ].
Although liposomal cipro has shown increased efficacy due to prolonged residence of cipro in the blood free cipro is cleared in minutes , the half-life of release from the liposomes was only 1 hour, yet the liposomes themselves circulated for more than 24 hours [ , ]. The therapeutic activity of vincristine is dictated by the duration of therapeutic concentrations at the tumor site [ , , ]. However, conventional liposomes, while offering improved bioavailability, also cannot encapsulate vincristine for sufficient time to give optimal results [ , , ]. Future work will determine if multiple compartment structures like vesosome give sufficient enhancement of small drug entrapment to lead to new therapeutics.
Genetics play an increasingly important role in medicine and is used routinely to diagnose diseases and to understand malfunctions at the molecular level. The active approach of trying to amend genetic defects or insufficiencies is a logical next step. Major elements in the successful advance of gene therapy are identification of the disease and target cells, tissues and organs as well as construction of appropriate gene vectors, effective gene transfer and expression in the targeted cells. Many inherited diseases follow the Mendelian inheritance pattern in which the cause is due to a single genetic defect.
Because the existing therapeutic treatments of such diseases are in most cases very limited, it is hoped that by transfecting appropriate cells with the correct gene or by adding a missing one, the disease could be alleviated. Examples of such potential treatments are for cystic fibrosis, hemophilia, sickle cell anemia or hypercholesterimia and mutant tumor suppressor genes.
The aim of gene therapy is to deliver DNA, RNA or antisense sequences to appropriate cells in order to alleviate symptoms or prevent the occurrence of a particular disease, i. The major approaches to gene therapy include gene replacement, addition of genes for production of natural toxins, stimulation of the immune system or over expression of highly immunogenenic genes for immune self-attack and sensitization of cells to other treatments.
Recently, the studies on gene delivery into eukaryotic cells by the use of non-viral-lipid-based macromolecular delivery systems have been experiencing a growing interest owing to the appearance of clinical protocols for gene therapy. Although the efficiency and specificity of such non-viral delivery systems are not yet very high, some of the problems concerning transfection methods are being successfully solved.
To date, the transfection mediators that ensure effective and directed gene delivery into various cells have been created. Transfection of plasmid DNA is closely connected to the problem of condensation of its molecule since the plasmid is too large kb to effectively overcome the cellular membrane barrier. Besides, free DNA has to be protected from destruction by endogenous nucleases. Lastly, it is necessary to neutralize the negative charge on DNA.
Genosomes are the artificial functional complexes for functional gene or DNA delivery to cell [ ]. For the production of genosomes, cationic phospholipids were found to be more suitable because they possess high biodegradability and stability in the blood stream. Gene delivery is a vast area of research and a detailed summary of work in that field is beyond the scope of this chapter. New generation liposomes and their features are summarized in Table 2. Extensively motivated by the need to increase the stability and bioavailability of drugs, and to reduce their side effects by targeting to the site of action, research in new drug delivery vehicles has taken giant steps.
Liposomes and their derivatives, so called new generation liposomes, present a vast area in this field where several advances have already been achieved as summarized in this chapter. However, still further research is required to overcome the limitations faced today in terms of prolonged stability, drug loading and active targeting. In the last decade from the concept of clinical utility of liposomes to their recognized position in mainstream of drug delivery systems, the path has been long and winding.
The liposome systems have been explored in the clinic for applications as diverse as sites of infection and imaging, for vaccine, gene delivery and small molecular drugs, for treatment of infections and for cancer treatment, for lung disease and for skin conditions etc. Several liposomal formulations are already on the market, while quite a few are still in the pipeline for treatment of diseases.
Conventional techniques for liposome preparation and size reduction remain popular as these are simple to implement and do not require sophisticated equipment. However, not all laboratory scale techniques are easy to scale-up for industrial liposome production. The need for improvements in the design and stability of liposomal diagnostic and therapeutic systems will continue to motivate innovative and efficient routes to their production.
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We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists. Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. Downloaded: Introduction Lipids are amphiphilic molecules, where one part of the molecule is water-loving hydrophilic and the other water-hating hydrophobic. Liposome preparation methods The manufactured liposome features are directly related to the preparation method. Mechanical agitation In this method, lipids are directly solubilized in water upon application of high mechanical agitation, through the use of probe sonication.
Solvent evaporation In general this method consists of four major steps; first is the solubilization of the lipid and a hydrophobic compound in an organic solvent; second is solvent evaporation; third is hydration with a buffer and the hydrophilic compound and if need the fourth often involves obtaining unilamellar liposomes from the obtained multilamellar ones. Solubilization of the lipid The starting point of this liposome preparation method is to prepare an organic solution of membrane lipids in order to ensure complete and homogenous mixing of all the components as they are required in the final membrane preparation.
Solvent evaporation The next step is the evaporation of the organic solvent.
ADVANCES IN LIPOSOMAL DRUG DELIVERY SYSTEM: FASCINATING TYPES AND POTENTIAL APPLICATIONS
Hydration Evaporation or freeze-drying of the solvent is followed by hydration of lipids with the aqueous medium. Obtaining SUVs from MLVs After preparation of MLVs by hydration of dried lipid, it is possible to continue processing the liposomes in order to modify their size and other characteristics.
Solvent injection In this type of preparation methods, lipids are first dissolved in an organic solvent and then brought into contact with the aqueous phase containing the materials to be encapsulated within the liposome. Ethanol injection method In this method an ethanol solution of lipids is injected rapidly into an excess saline or other aqueous medium by a fine needle [ 38 ]. Ether injection method This method [ 39 , 40 ] involves injecting the immiscible organic solution very slowly into an aqueous phase through a narrow needle at a temperature that the organic solvent is removed by vaporization during the process.
Surfactant detergent solubilization method In this method, the phospholipids are brought into contact with the aqueous phase via the intermediary of surfactants. Loading of drugs in liposome formulations 2. Encapsulation of hydrophilic drugs Once lipids are hydrated in the presence of hydrophilic drugs, a portion of the drug gets entrapped inside the liposome and another portion remains in the bulk, outside the aqueous core of the liposome. Encapsulation of hydrophobic drugs Hydrophobic drugs are solubilized in the phospholipid bilayer of the liposomes that mainly provide a hydrophobic environment.
Stability of liposomes Liposome stability can be explained by physical, chemical and biological means which are all interrelated. Sterilization of liposomes Pharmaceutical industry in general differentiates between two principally different approaches to ensure sterility of a parental product: terminal sterilization of the final product in its container steam sterilization and aseptical manufacturing. Table 1. Characterization of liposomes After preparation and before application, liposomes have to be characterized in order to ensure their in vitro and in vivo performance.
Clinical applications of liposomes New drug delivery systems such as liposomes are developed when the existing formulations are not satisfactory. Ocular applications The eye is protected by three highly efficient mechanisms a an epithelial layer which is the barrier to penetration b tear flow c the blinking reflex. Pulmonary applications Lung is a natural target for the delivery of therapeutic and prophylactic agents such as peptides and proteins.
Cancer therapy The numerous anti-cancer agents that have a high cytotoxic effect on the tumor cells in vitro exhibit a remarkable decrease of the selective ant-tumor effect for in vivo procedures applicable in the clinical treatment. This method is still occasionally used today, and is referred to as viral gene delivery. Non-viral gene delivery, however, has become popular over the last 20 years due to enhanced safety profiles, lower rates of adverse immunogenic reactions and ease of manufacturing. One of the primary drivers of this movement has been the development of lipid and polymer-based carriers, of which LNPs are the most popular.
LNPs used to deliver genes are primarily synthesized using cationic, or positively-charged, lipids that associate with anionic, or negatively-charged, nucleic acids. Other lipid-based components can also be added to modulate the delivery efficiency and location release of the genetic cargo. LNPs also provide mechanical stability, controlled morphology and narrow size distribution.
Inorganic materials, organic materials and hydrogels have each been explored as cores for liposomal nanoparticles , encapsulated within varying numbers of lipid layers that form the shell. These two core biopolymers are particularly useful in drug delivery because they facilitate controlled drug release. Meanwhile, understanding [of] the interactions between these nanostructures and biological systems is rapidly progressing. A substantial amount of information on their circulation time, tissue accumulation, and potential toxicity has been obtained.
It is certain that liposome-like nanocarriers will play a larger role for drug delivery in the foreseeable future. While there is significant work ongoing in the development of controlled-release, nano-compartmentalized medicinal agents, liposomes and LNPs are especially promising options. These structures provide a unique, naturally stable, cell-like morphology for nanomedicines, and are poised to progress towards more advanced therapeutic strategies.
Liposomal Drug Delivery Systems: An Update Review
Exelead is taking on such challenges, including the development of nanogels that incorporate an array of biologics and small molecules. Since liposomes were first proposed as a drug delivery system in the late s, variations in structure and functionality have emerged, providing valuable advancements in terms of disease targeting. LNP drugs have cropped up across the pharmaceutical industry as therapies designed to deliver anti-cancer agents, antibiotics, gene medicines, anesthetics and anti-inflammatory drugs.
This has resulted in an overall increase in therapeutic index, which measures efficacy over toxicity. This is extremely applicable for diseases like cancer. Even within a single type of cancer, tumor types differ from one patient to another, and understanding the particular genetic mutation a patient has developed allows doctors to employ more specific and precise treatments. This approach to hyper-specific disease targeting increases efficacy and decreases unwanted side effects for groups of similar patients. Because so much of the growing field of personalized medicine is focused on genetic therapies, LNPs have become particularly useful as a drug delivery platform.
Any oligonucleotide could theoretically be encapsulated within a liposome or LNP, but siRNA are currently the most common cargo in these types of drug products. In theory, segments of siRNA can be designed to silence any gene, which is an exciting concept for both doctors and researchers.
Unfortunately, delivery of free, unencapsulated RNA into human cells is difficult, as they are large, unstable in serum and prone to nuclease degradation. While researchers have made attempts to stabilize siRNA in serum by adding phosphorothioate linkages, high doses are required to effectively silence genes in humans. LNPs have provided a solution to this problem by providing flexible and easy means of encapsulation , protecting the siRNA segments until they reach their intended destination and facilitating their delivery into target cells.
In contrast, traditional manufacturing batches for mainstream pharmaceuticals often produce thousands of liters of drug product at scale. Personalized medicine requires a unique approach, and each batch must be manufactured under stringent cGMP conditions.
As personalized medicine has become a prominent focus in drug development, many companies in the pharmaceutical manufacturing industry have adapted their pipelines to accommodate smaller batches slated for small groups of patients in addition to traditional, large-scale drug production. At Exelead, extensive efforts have been made to accommodate these small-batch therapeutics, which often require expensive API and quick turnaround time.
These short-term forecasts, sometimes only six weeks, present challenges that we have been able to overcome by refining our existing systems and incorporating innovative formulation techniques. While personalized medicine has the potential to treat almost any disease, current research has primarily focused on 1 immunotherap ies , 2 conventional therapies augmented via pharmacogenomics and 3 biomarker-related cancer treatments.
Liposomes and LNPs have application as delivery vehicles for each of these categories of drug products, making them an indispensable asset in this new field of pharmaceutical development. About Us Resources News Careers. Search this site on Google Search Google. What are liposomes, and how are they used in drug delivery? Liposomes vs. LNPs in gene therapy For a long time, the most effective way to deliver gene-based therapeutics to human cells was to use a virus that had been modified to carry medicinal cargo rather than harmful, self-replicating genes.
LNPs as delivery vehicles for oligonucleotides Because so much of the growing field of personalized medicine is focused on genetic therapies, LNPs have become particularly useful as a drug delivery platform. Widespread applications While personalized medicine has the potential to treat almost any disease, current research has primarily focused on 1 immunotherap ies , 2 conventional therapies augmented via pharmacogenomics and 3 biomarker-related cancer treatments.
Liposome-like Nanostructures for Drug Delivery. Journal of materials chemistry B, Materials for biology and medicine. Journal of pharmaceutical sciences. Allen, Pieter R. Liposomal drug delivery systems: From concept to clinical applications.