Chapter

Liposomes as a Drug Delivery System

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Abstract

The discovery of phospholipids spontaneously forming spherical, self-closed bubbles known as liposomes, upon dispersion in water, ushered a new era in drug delivery technology. Continuous and systematic research over the last few decades has resulted in the development of tailor-made liposomal formulations * Authors contributed equally.

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... Liposomes are spherical vesicles of 0.05-5.0 µm in diameter formed by two layers, where the aqueous volume is surrounded by a membranous lipid bilayer composed of natural or synthetic phospholipids, such as cholesterols, non-toxic surfactants, sphingolipids, glycolipids, chain long fatty acids, and even membrane proteins (103)(104)(105). These liposomal systems can be encapsulated with lipophilic drugs and can be used in diseases such as cancer (103)(104)(105). ...
... µm in diameter formed by two layers, where the aqueous volume is surrounded by a membranous lipid bilayer composed of natural or synthetic phospholipids, such as cholesterols, non-toxic surfactants, sphingolipids, glycolipids, chain long fatty acids, and even membrane proteins (103)(104)(105). These liposomal systems can be encapsulated with lipophilic drugs and can be used in diseases such as cancer (103)(104)(105). They can also transport water and non-ionic substances, thus offering protection against oxidative wear, improving the stability of linked drugs and controlling the hydration of the molecule (103)(104)(105). ...
... These liposomal systems can be encapsulated with lipophilic drugs and can be used in diseases such as cancer (103)(104)(105). They can also transport water and non-ionic substances, thus offering protection against oxidative wear, improving the stability of linked drugs and controlling the hydration of the molecule (103)(104)(105). Liposomes release the drug in a sustained way so as to improve its pharmacokinetics, reducing the dose necessary for a therapeutic effect and causing a decrease in toxicity. ...
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... They can combat the disadvantages of other delivery systems by protecting the drugs from several types of resistance such as enzymes from the body (from mouth to stomach), stomach acids, bile salts, and free radicals (Akbarzadeh et al., 2013). The main aim of a liposomal delivery system is to provide a high therapeutic index and to increase the half-life of the entrapped drug, since they are stable in both in vitro and in vivo and have a high systemic residence time and improved sustained release of therapeutics (Banerjee et al., 2015). ...
... For example, "stealth liposomes" have an extended half-life, which masks them from being recognized by RES. They provide a steric barrier with blood components at the surface of the liposome (Banerjee et al., 2015). ...
... 3 Approved Liposomal Drugs on the Market for Human Use(Banerjee, 2015; Allen, 2013) ...
... However, the high hydrophobicity of apigenin poses an impediment in its direct usage as a chemotherapeutic agent in conventional methods for treating cancer; hence it is an interesting candidate for drug delivery application. A liposomal nanocarrier bearing the anti-tumorigenic agent apigenin was designed in this study in order to improve the bioavailability of the flavone [7,8]. ...
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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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Equilibrium swelling curves of N‐isopropylacrylamide (NIPA) gel and a series of its ionized counterparts were measured as a function of temperature. Nonionic NIPA gels underwent a sharp yet continuous volume change, whereas incorporation of a small amount of ionizable groups into the gel network drives the transition toward a discontinuous one. The critical ionic concentration and polymer network density at which the get undergoes a critical phase transition were determined. The results were analyzed using a mean field theory. Discrepancy between experimental data and theory is nontrivial, and may require the formulation of a more elaborate theory.
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Three samples of poly(2-ethylacrylic acid) (PEAA) of different molecular weights (M_w = 164000, 43000, and 12000) were prepared by radical polymerization of 2-ethylacrylic acid in bulk. The conformational properties of the samples were determined and correlated with the pH-dependent structural reorganization observed in phosphatidylcholine vesicles suspended in the respective polymer solutions. In all experiments the sample of lowest molecular weight behaved differently from the other two: The cooperativity of the conformational transition was reduced and the transition midpoint was shifted to lower pH as compared to the samples of higher molecular weight. These effects of polymer molecular weight were reflected in the behavior of the vesicle-to-micelle transition observed upon acidification of aqueous mixtures of PEAA and dipalmitoylphosphatidylcholine.
Article
The microstructures of severed copolymers of styrene and N-vinylimidazole in dilute solutions and cast films were investigated by fluorescence, 13C NMR, light scattering, viscosity, and electron microscopy. Random sequence distribution of the copolymers was characterized by 13C NMR. Despite such random distribution of the styrene and imidazole groups along the chain, phase separation of the hydrophobic styrene and the hydrophilic imidazole domains is suggested by several experimental findings. Smaller hydrodynamic volumes of such styrene-imidazole copolymers in polar solvents were measured compared to those for the homopolymer, poly(N-vinylimidazole), at comparable molecular weights. This is attributed to the aggregation of styrene residues in the polar environment. A sharp conformational change of these copolymers in aqueous media from a supercoiled dispersion to a water-soluble extended coil can be induced by protonation of the imidazole moiety. Local aggregation of the styrene groups and electrostatic repulsion of the protonated imidazolium groups are the causes for such a transition. The styrene aggregation was further characterized by the styrene emission spectra of the copolymers. The excimer-to-monomer peak ratio of the intrinsic styrene chromophore varies with copolymer composition, solvent, and pH, suggesting the effect of long-range interaction on styrene excimer formation. Separation between the styrene and imidazole domains was further verified by the absence of energy transfer from the styrene chromophore as the donor to an acceptor probe, 1-pyrenesulfonic acid, complexed at the imidazole site. Such phase separation is manifested in films cast on water from organic solutions of the copolymers. These results suggest that the hydrophobic/hydrophilic random copolymers behave as polymeric surfactants characterized by a micellelike structure in an aqueous environment.
Article
The fluorescence spectroscopy of pyrene-labeled (hydroxypropyl)cellulose in water was examined as a function of temperature from 25 to 65°C. The intense excimer emission observed at 25°C increased slightly from 25 to 35°C then decreased sharply before the cloud point of the polymer. The results are interpreted in terms of changes in two different interactions of the polymer with water: the hydrophobic interactions between pyrene groups and the hydrogen bonding of water molecules with the polymer hydroxypropyl substituents. A large solvent isotope effect on the excimer emission intensity, turbidity measurements and fluorescence measurements on a polymer with very low label incorporation give further support to this interpretation.
Article
Poly (acrylic acid), poly(methacrylic acid), and poly(α-ethylacrylic acid) can be used to modify, in a pH-dependent manner, the properties of phospholipid vesicle membranes. Polymer-lipid complexation causes a decrease in the apparent cooperativity of the lipid melting transition. The "critical pH" for complexation may be controlled through variation of the chemical structure and the tacticity of the poly(carboxylic acid). It is suggested that an important driving force for complexation is provided by the formation of hydrogen bonds between un-ionized carboxyl groups of the polymer and the phosphodiester functions of the lipid surface.
Article
Differential scanning calorimetry (DSC) was performed on aqueous solutions of poly(N-isopropylacrylamide-co-butyl methacrylate-co-X), with X being hydrophilic, hydrophobic, cationic, or anionic comonomers, to elucidate the mechanism of temperature-induced phase separation and the effect of comonomer content, hydrophilicity, and charge on the lower critical solution temperature (LCST). The endothermic heat of phase separation, which is related to the breaking of hydrogen bonds between water molecules surrounding hydrophobic moieties on the polymer, was a linear, decreasing function of the LCST. This suggests that the hydrophobic interactions between polymer side groups, which are the major driving force for phase separation, are enhanced at elevated temperatures due to a decrease in the structuring of water around hydrophobic side groups. It is concluded that the changes in LCST caused by the incorporation of comonomers are due to changes in overall hydrophilicity of the polymer and are not due to a direct influence of comonomer hydrophilicity or charge on the structuring of water around hydrophobic groups.
Article
A lipophilic chain transfer reagent was prepared by coupling of N,N-dioctadecylamine with 3-mercaptopropionic acid, and telomerization of acrylic acid (product, DODA-S-PAA) or N-isopropylacrylamide (product, DODA-S-PIPA) was carried out by using the chain transfer reagent. The amphiphiles obtained formed stable liposomes with lecithin (L-alpha-dimyristoylphosphatidylcholine or L-alpha-dipalmitoylphosphatidylcholine), and the liposomes showed a pH-responsive (DODA-S-PAA) or temperature-responsive (DODA-S-PIPA) release of fluorophore from inner water pool. The lipophilic chain transfer reagent was useful to prepare amphiphiles with various functionalities.
Article
Most pharmaceutical and gene therapy applications of targeted liposomes presently suffer from inefficient contents delivery to the cytoplasm of target cells. We report a plasma-stable liposome, composed of synthetic, naturally occurring diplasmenylcholine (1,2-di-O-(Z-1‘-hexadecenyl)-sn-glycero-3-phosphocholine; DPPlsC), that rapidly and efficiently releases its contents at endosomal pHs. Acid-catalyzed hydrolysis of these liposomes produces glycerophosphocholine and fatty aldehydes, leading to greatly enhanced liposome permeability (t50% release 1−4 h between pH 4.5−5.5) when >20% of the vinyl ether lipid has been hydrolyzed. Plasma stability of nonhydrolyzed 9:1 DPPlsC/dihydrocholesterol liposomes exceeds 48 h at 37 °C, pH 7.4 in 50% serum; pure DPPlsC liposomes remain stable in 10% serum under the same conditions. Fluorescence assays of KB cells treated with 99.5:0.5 DPPlsC/DSPE−PEG3350−folate liposomes containing encapsulated propidium iodide (PI) indicate that 83% of the PI escapes the endosomal compartment within 8 h to produce intensely stained nucleii. The IC50 value of 1-β-arabinofuranosylcytosine (Ara-C) encapsulated in DPPlsC/DSPE−PEG3350−folate liposomes is 0.49 μM in KB cell cultures, a 6000-fold enhancement in cytotoxicity compared with free drug (2.8 mM). Empty DPPlsC/DSPE−PEG3350−folate liposomes had no effect on DNA synthesis, indicating that DPPlsC and its degradation products are benign to cell function at these lipid concentrations. Our results suggest that concurrent application of selective targeting and membrane translocation mechanisms in drug carriers can significantly increase their efficacy.
Article
We have shown that the hydrophobic polyelectrolyte poly-(2-ethylacrylic acid) (PEAA, 1) causes destabilization of lipid bilayer membranes at pH 6.55 or lower and that this pH-sensitive [compound 1] response can be used to trigger release of hydrophilic compounds entrapped in liposomes. Responsive membrane systems are finding increasingly important applications in drug delivery, signal amplification in biochemical assay, and molecular recognition.
Article
A sensitive solution microcalorimeter was used to study lower critical solution temperatures (LCSTs) of aqueous polymer solutions. Endotherms with enthalpies on the order of the strength of hydrogen bonds were observed at temperatures concurring with LCSTs detected by classical cloud-point measurements for solutions of poly(iY-isopropylacrylamide) (PNIPAAM), poly(vinyl methyl ether) (PVME), polypropylene glycol) (PPG), and hydroxypropylcellulose (HPC). The LCST of PNIPAAM was found to be dependent on the chain length, generally increasing with decreasing M̄n in the range M̄n = 1.6 × 105 to 5.4 × 103. Treatment of the calorimetric endotherm according to a two-state transiton model afforded cooperative unit sizes of the order of the chain length for PNIPAAM, PVME, and PPG. The apparent cooperative unit for the demixing transition of HPC was found to be larger than a single chain, consistent with previous observations of aggregation of HPC below the LCST. Depression of the LCST by added salts was observed.