RESUMO
Biomimetic nanoparticles based on polysaccharides-poly(alkylcyanoacrylates) copolymers were initially developed in view of drug delivery. Core-shell nanoparticles covered with a sufficiently long brush of polysaccharides were shown to be very low complement activators and have the potential for long circulation times in the bloodstream. Such nanoparticles bearing haemoglobin were envisaged as potential red cell substitutes. Different core-shell nanoparticles with a brush shell made of dextran, dextran-sulphate, or heparin were prepared and haemoglobin (Hb) could be adsorbed on their surface. Benzene tetracarboxylic acid (BTCA) was used as a coupling agent for Hb to dextran-coated nanoparticles; the Hb loading capacity of the dextran nanoparticles showed a 9.3 fold increased. The coupled Hb maintained the allosteric properties of free Hb. While modification of nanoparticles by BTCA slightly increased complement activation, the further addition of Hb totally reversed this effect providing Hb-loaded nanoparticles with a very low level of complement activation. Such nanoparticles could be a suitable alternative to haemoglobin solutions in the development of a blood substitute.
Assuntos
Cianoacrilatos/química , Nanopartículas , Oxigênio/administração & dosagem , Polímeros/química , Polissacarídeos/químicaRESUMO
Progress in developing a blood substitute is aided by new biotechnologies and a better understanding of the circulatory system. For Hb based solutions, there is still a debate over the best set of fundamental parameters concerning the oxygen affinity which is correlated with the oxidation rate, the cooperativity, the transporter size, and of course the final source of material. Genetic engineering methods have helped discover novel globins, but not yet the quantity necessary for the high demand of blood transfusions. The expanding database of globin properties has indicated that certain individual parameters are coupled, such as the oxygen affinity and the oxidation rate, indicating that one must accept a compromise of the best parameters. After a general introduction of these basic criteria, we will focus on two strategies concerning the size of the oxygen transporter: Hb octamers, and Hb integrated within a nanoparticle.
Assuntos
Substitutos Sanguíneos/uso terapêutico , Hemoglobinas/uso terapêutico , Nanopartículas/uso terapêutico , Transporte Biológico , Substitutos Sanguíneos/síntese química , Substitutos Sanguíneos/química , Engenharia Genética/métodos , Vetores Genéticos , Globinas/química , Globinas/genética , Globinas/uso terapêutico , Haptoglobinas/química , Haptoglobinas/genética , Haptoglobinas/uso terapêutico , Hemoglobinas/química , Hemoglobinas/genética , Humanos , Cinética , Preparações Farmacêuticas/administração & dosagem , Polissacarídeos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêuticoRESUMO
Polymer nanoparticles are designed as nanovehicles to carry drugs in the body in a controlled manner increasing the concentration of the biologically active substance in the diseased organs and cells. The safety and biocompatibility of these nanosystems are those of the many properties that nanoparticles must meet to be used in vivo. Here we show that the cytotoxicity profile of poly(isobutylcyanoacrylate) (PIBCA) nanoparticles is affected by the way the nanosystems were produced and by the design of their surface. It was found that the tolerance of PIBCA nanoparticles by cells could be improved up to 100-fold by coating their surface with polysaccharides and haemoglobin.
Assuntos
Cianoacrilatos/química , Dextranos/química , Nanopartículas/química , Polímeros/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Cianoacrilatos/toxicidade , Embucrilato , Leucemia P388/patologia , Camundongos , Polímeros/toxicidade , Propriedades de SuperfícieRESUMO
A new generation of drug delivery systems based on heparin-poly(isobutylcyanoacrylate) copolymers has been developed to carry hemoglobin. These copolymers spontaneously form, in water, nanoparticles with a ciliated surface of heparin. These nanoparticles maintain the heparin antithrombotic properties and inhibit complement activation. One ml of nanoparticle suspension can be loaded with up to 2.1mg of hemoglobin, which preserves its ligand binding capacity. This work constitutes the first demonstration of hemoglobin loaded on nanoparticle surface, rather than being encapsulated. With a size of 100 nm, these drug delivery systems make suitable tools in the treatment of thrombosis oxygen deprived pathologies.
