RESUMO
The effect of 5-n-alkylresorcinols, natural amphiphilic compounds, upon properties of phospholipid vesicles depends on their localization asymmetry. A significant increase of the bilayer permeability is observed when the title compounds are present only in the external medium. When these amphiphiles are preincorporated into the bilayer during its formation, the resulting liposomes effectively encapsulate water-soluble solutes which still remain in liposomes after 25 h. Additionally, the size of liposomes made of alkylresorcinol-phosphatidylcholine mixtures after eight cycles of freezing and thawing only (180-200 nm) is severalfold smaller than the size of vesicles prepared in a similar way from phospholipids only and the resulting liposomes are more homogeneous. These liposomes modified with alkylresorcinols are also stable during 40 day storage at both 4 degrees C and 20 degrees C, in contrast to control liposomes that already strongly aggregate after 10 days.
Assuntos
Lipossomos/química , Resorcinóis/química , Bicamadas Lipídicas/química , Lipossomos/ultraestrutura , Tamanho da Partícula , Permeabilidade , Fosfatidilcolinas/química , Temperatura , Fatores de TempoRESUMO
Almost from the time of their rediscovery in the 60's and the demonstration of their entrapment potential, liposomal vesicles have drawn attention of researchers as potential carriers of various bioactive molecules that could be used for therapeutic applications in humans and animals. Several commercial liposome-based drugs have already been discovered, registered and introduced with great success on the pharmaceutical market. However, further studies, focusing on the elaboration of more efficient and stable amphiphile-based vesicular (or non-viral) drug carriers are still under investigation. In this review we present the achievements of our group in this field. We have discovered that natural amphiphilic dihydroxyphenols and their semisynthetic derivatives are promising additives to liposomal lipid compositions. The presence of these compounds in lipid composition enhances liposomal drug encapsulation, reduces the amount of the lipid carrier necessary for efficient entrapment of anthracycline drugs by a factor of two, stabilizes liposomal formulation of the drug (both in suspension and in a lyophilized powder), does not influence liposomal fate in the blood circulation system and benefits from other biological activities of their resorcinolic lipid modifiers.
Assuntos
Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Lipossomos , Antraciclinas/administração & dosagem , Biotecnologia , Lipossomos/química , Fosfolipídeos , Resorcinóis , TensoativosRESUMO
Three new groups of phenolic antioxidants, quaternary ammonium salts with a phenol ring and alkyl chains of different length (pyrrolidine ethyl esters of 3,5-di-t-butyl-4-hydroxydihydrocinnamic acid n-alkoxymethylchlorides (PYE-n) or n-alkylbromides (PYA-n) and 2-dimethylaminoethyl ester n-alkylbromides (PPA-n), were synthesized. Some of them were previously found to efficiently protect yeast cells against oxidants and to inhibit the production of thiobarbituric acid-reactive substances in whole yeast cells and in isolated membrane lipids. The new antioxidants (at 1-100 microM) abolished or diminished peroxidation of olive oil emulsions caused by the OH*-producing Fe2+ and RO* and ROO*-producing tert-butylhydroperoxide (TBHP) and the azo compounds 2,2'-azobis-(amidinopropane)dihydronitrile (AAPH) and 1,1'-azobis-(1-cyclohexanecarbonitrile) (ACHN): all present at 10 mM. The efficiency of individual both antioxidants was examined in relation to the type of lipid peroxidation inducer, the site of antioxidant incorporation into the emulsion lipid phase, the length of the alkyl chain, and the maximum concentration of effective antioxidant monomers given by its critical micelle concentration. PYA-n class compounds were highly efficient against all peroxidation inducers and their efficiency did not depend on the position of their molecules in the lipid phase and/or on the aliphatic chain length. In contrast, the efficiency of PYE-n and PPA-n class compounds depended both on the type of oxidant and on the length of their aliphatic chain. Their potency against Fe2+ and ACHN increased with increasing alkyl chain length whereas with AAPH it dropped with increasing alkyl chain length. A similar pattern was found with the action of PYE-n against TBHP whereas in the PPA-n group an extending alkyl chain reduced the anti-TBHP efficiency. These relationships may not be entirely straightforward and other factors (chemical nature of each compound, its possible interaction with fluorescent probes used for diagnostics, etc.) may play a considerable and not yet quite clear role. PPA-n class antioxidants have the lowest critical micelle concentration, which may limit their efficiency. Nevertheless, these phenolic antioxidants can be conveniently employed as highly efficient inhibitors of lipid peroxidation.
Assuntos
Antioxidantes , Cinamatos/química , Peroxidação de Lipídeos , Compostos de Amônio Quaternário/química , Antioxidantes/química , Corantes Fluorescentes , Radicais Livres , Cinética , Peroxidação de Lipídeos/efeitos dos fármacos , Modelos Biológicos , Azeite de Oliva , Oxidantes/química , Óleos de Plantas , Relação Estrutura-Atividade , Tensão Superficial , TriglicerídeosRESUMO
Alkylresorcinolic lipids isolated from cereal grains and their semi-synthetic myristoyl-sulphonyl derivatives (MSAR) were used to modify small long-circulating sphingomyelin-cholesterol liposomes. Those SM:Chol vesicles modified with 10-30 mol% resorcinolic lipids had stable size and low membrane permeability in vitro at 4 degrees C and 37 degrees C. Liposomes containing 30 mol% MSAR showed very fast solute release in the presence of human plasma at 37 degrees C, which was drastically diminished in heat-inactivated plasma. In vivo studies showed that unmodified SM:Chol liposomes and those modified with alkylresorcinols were eliminated from the circulation more slowly than liposomes with the highest concentration of MSAR in membrane and were located mostly in the liver and spleen.