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- Liposomes as a Model for the Biological Membrane: Studies on Daunorubicin Bilayer InteractionPublication . Matos, Carla; Moutinho, Carla; Lobão, PauloIn this study the interaction of the antitumoral drug daunorubicin with egg phosphatidylcholine (EPC) liposomes, used as a cell membrane model, was quantified by determination of the partition coefficient (K(p)). The liposome/aqueous-phase K(p) of daunorubicin was determined by derivative spectrophotometry and measurement of the zeta-potential. Mathematical models were used to fit the experimental data, enabling determination of K(p). In the partition of daunorubicin within the membrane both superficial electrostatic and inner hydrophobic interactions seem to be involved. The results are affected by the two types of interaction since spectrophotometry measures mainly hydrophobic interactions, while zeta-potential is affected by both interpenetration of amphiphilic charged molecules in the bilayer and superficial electrostatic interaction. Moreover, the degree of the partition of daunorubicin with the membrane changes with the drug concentration, due mainly to saturation factors. Derivative spectrophotometry and zeta-potential variation results, together with the broad range of concentrations studied, revealed the different types of interactions involved. The mathematical formalism applied also allowed quantification of the number of lipid molecules associated with one drug molecule.
- Correlation between octanol/water and liposome/water distribution coefficients and drug absorption of a set of pharmacologically active compoundsPublication . Esteves, Freddy; Moutinho, Carla; Matos, CarlaAbsorption and consequent therapeutic action are key issues in the development of new drugs by the pharmaceutical industry. In this sense, different models can be used to simulate biological membranes to predict the absorption of a drug. This work compared the octanol/water and the liposome/water models. The parameters used to relate the two models were the distribution coefficients between liposomes and water and octanol and water and the fraction of drug orally absorbed. For this study, 66 drugs were collected from literature sources and divided into four groups according to charge and ionization degree: neutral; positively charged; negatively charged; and partially ionized/zwitterionic. The results show a satisfactory linear correlation between the octanol and liposome systems for the neutral (R²= 0.9324) and partially ionized compounds (R²= 0.9367), contrary to the positive (R²= 0.4684) and negatively charged compounds (R²= 0.1487). In the case of neutral drugs, results were similar in both models because of the high fraction orally absorbed. However, for the charged drugs (positively, negatively, and partially ionized/zwitterionic), the liposomal model has a more-appropriate correlation with absorption than the octanol model. These results show that the neutral compounds only interact with membranes through hydrophobic bonds, whereas charged drugs favor electrostatic interactions established with the liposomes. With this work, we concluded that liposomes may be a more-appropriate biomembrane model than octanol for charged compounds.
- Encapsulação de dois fármacos anticancerígenos (5-fluorouracilo e metotrexato) em lipossomas unilamelaresPublication . Conceição, Ana Isabel F. S.; Matos, Carla; Moutinho, CarlaEste trabalho descreve os resultados preliminares da eficiência de encapsulação de dois fármacos anticancerígenos em liposomas com o intuito de desenvolver uma formulação de cedência modificada. Apresentam-se os resultados da determinação da eficiência de encapsulação de dois anticancerígenos (5-fluorouracilo e metotrexato) em lipossomas unilamelares (LU V) de fosfatidilcolina da gema do ovo (EPC). Estes fármacos foram escolhidos pois, muito embora sejam utilizados há já várias décadas apresentam, no entanto, dificuldades na sua utilização (absorção variável, biodisponibilidade incompleta) e efeitos secundários graves, podendo ser um benefício a sua inclusão em lipossomas. Estes foram preparados pelo método clássico da hidratação do filme lipídico e extrudidos por filtros de policarbonato de 100 nm de diâmetro de poro. A eficiência de encapsulação foi determinada após separação do fármaco não encapsulado por centrifugação, usando tubos de separação Amicon. This work describes preliminary results for the encapsulation efficiency of two anticancer drugs in liposomes in order to develop a controlled delivery formulation. Results for the encapsulation efficiency of 5-fluorouracil and methotrexate, in egg phosphatidylcholine (EPC) large unilamellar vesicles (LU V) are presented. The drugs were chosen because, although available for many years, present difficulties in administration (variable absorption, incomplete bioavailability), besides severe in vivo toxicity, and its inclusion in liposomes may be benefic. The liposomes were prepared by the classical Bangham´s method of lipid film hydration, followed by extrusion through polycarbonate membranes. The encapsulation efficiency was determined after separation of the non entrapped drug by means of a ultrafiltration procedure, using Amicon ultra centrifugal filter devices.
- Development of innovative nanotechnology-based drug delivery systems for cancer therapyPublication . Moutinho, Carla; Matos, Carla; Balcão, VictorControlled drug delivery systems are not a new subject in the biomedical field. The continuously increasing need for the improvement of health care services has been the driving force for both search and development of such systems. Among these, micro- and nano-sized vehicles (e.g. nanocapsules, liposomes and mixed micelles) have received special attention over the last decade; they have been used for the delivery and vectorization of many pharmacologically active molecules, as is the case of anti-neoplastic drugs.
- Interacção de fármacos com lipossomas: áreas de aplicaçãoPublication . Matos, Carla; Moutinho, CarlaOs lipossomas têm a capacidade de simular muitas das propriedades das membranas celulares, constituindo ferramentas valiosas para o estudo das consequências da interacção fármaco-lípido a nível das propriedades físico-químicas e estruturais, quer da membrana quer do fármaco e respectivos efeitos no mecanismo de acção deste. Por outro lado, devido à singular morfologia e capacidade de intervir em fenómenos de transporte na bicamada fosfolipídica, o uso de lipossomas como transportadores de fármacos tem sido largamente estudado. Liposomes are able to simulate many of the properties of cell membranes, providing valuable tools for the study of drug-lipid interaction consequences. Such consequences can be changes on whether the membrane’s or the drug’s physical-chemical and structural properties, and its effects on the action mechanism of the latter. Furthermore, due to natural morphology and ability to intervene in the transport phenomena in phospholipic bilayer, the use of liposomes as carriers of drugs has been widely studied.
- Nanocarrier possibilities for functional targeting of bioactive peptides and proteins:state-of-the-artPublication . Moutinho, Carla; Matos, Carla; Teixeira, José A.; Balcão, VictorThis review attempts to provide an updated compilation of studies reported in the literature pertaining to production of nanocarriers encasing peptides and/or proteins, in a way that helps the reader direct a bibliographic search and develop an integrated perspective of the subject. Highlights are given to bioactive proteins and peptides, with a special focus on those from dairy sources (including physicochemical characteristics and properties, and biopharmaceutical application possibilities of e.g. lactoferrin and glycomacropeptide), as well as to nanocarrier functional targeting. Features associated with micro- and (multiple) nanoemulsions, micellar systems, liposomes and solid lipid nanoparticles, together with biopharmaceutical considerations, are presented in the text in a systematic fashion.
- Lipossomas: vectores atractivos e versáteis para o direccionamento de (bio)fármacosPublication . Conceição, Ana Isabel F. S.; Matos, Carla; Moutinho, Carla; Balcão, VictorOs lipossomas são microsistemas constituídos por uma ou mais bicamadas lipídicas dispostas esfericamente, separadas por fases aquosas, cujo cerne é um compartimento aquoso. Tais estruturas esféricas fechadas, cujo diâmetro varia tipicamente entre os 50 nm e os 5 mm, formam-se espontaneamente quando alguns lípidos são colocados em solução aquosa. Logo após a sua descoberta, na década de sessenta, surgiu a ideia de que poderiam ser usados como transportadores de compostos farmacologicamente activos, dado serem constituídos por compostos naturais, relativamente não-tóxicos e biodegradáveis. Liposomes are microsystems constituted by one or more lipid bilayers, arranged spherically, separated by aqueous phases, with an aqueous core. Such closed spherical structures, typically ranging in diameter from 50 nm to 5 mm, form spontaneously when certain lipids are placed in aqueous solution. Right after their discovery in the sixties, the idea that they could work as carriers for active drugs arose within the scientific community, since they are composed of natural compounds which are relatively non-toxic and biodegradable.