RESUMO
Most of DNA synthetic complexes result from the self-assembly of DNA molecules with cationic lipids or polymers in an aqueous controlled medium. However, injection of such self-assembled complexes in medium like blood that differ from that of their formulation leads to strong instability. Therefore, DNA vectors that have physico-chemical properties and structural organisation that will not be sensitive to a completely different medium in terms of ionic and protein composition are actively sought. To this end, the goal here was to discover and optimize a nanostructured system where DNA molecules would be encapsulated in nanocapsules consisting in an oily core and a shell covered by PEG stretches obtained through a nanoemulsion process in the absence of organic solvent. This encapsulation form of DNA molecules would prevent interactions with external hostile biological fluid. The results show the entrapment of lipoplexes into lipid nanocapsules, leading to the formation of neutral 110 nm-DNA nanocapsules. They were weakly removed by the immune system, displaying an increased blood half-life, and improved carcinoma cell transfection, in comparison to the parent lipoplexes. Our results demonstrate that the fabrication of nanocapsules encapsulating hydrophilic DNA in an oily core that meet criteria for blood injection is possible.
Assuntos
Materiais Biomiméticos , DNA/administração & dosagem , Vetores Genéticos , Lipossomos/química , Nanocápsulas/química , Animais , Células COS/metabolismo , Cátions , Chlorocebus aethiops , Microscopia Crioeletrônica , DNA/farmacocinética , Composição de Medicamentos/métodos , Emulsões , Ácidos Graxos Monoinsaturados/química , Feminino , Glicerol/análogos & derivados , Glicerol/química , Meia-Vida , Células HeLa/metabolismo , Humanos , Lipossomos/farmacocinética , Teste de Materiais , Camundongos , Nanocápsulas/análise , Ácidos Oleicos/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Polimetil Metacrilato/química , Compostos de Amônio Quaternário/química , Ácidos Esteáricos/química , Triglicerídeos/química , Zimosan/químicaRESUMO
Initially, gene therapy was viewed as an approach for treating hereditary diseases, but its potential role in the treatment of acquired diseases such as cancer is now widely recognized. The understanding of the molecular mechanisms involved in cancer and the development of nucleic acid delivery systems are two concepts that have led to this development. Systemic gene delivery systems are needed for therapeutic application to cells inaccessible by percutaneous injection and for multi-located tumor sites, i.e. metastases. Non-viral vectors based on the use of cationic lipids or polymers appear to have promising potential, given the problems of safety encountered with viral vectors. Using these non-viral vectors, the current challenge is to obtain a similarly effective transfection to viral ones. Based on the advantages and disadvantages of existing vectors and on the hurdles encountered with these carriers, the aim of this review is to describe the "perfect vector" for systemic gene therapy against cancer.
Assuntos
Cátions/química , Terapia Genética/métodos , Vetores Genéticos/química , Neoplasias/terapia , Vetores Genéticos/genética , Humanos , Lipídeos/química , Modelos Teóricos , Estrutura Molecular , Polímeros/químicaRESUMO
Over the last few decades, colloidal drug delivery systems (CDDS) such as nano-structures have been developed in order to improve the efficiency and the specificity of drug action. Their small size permits them to be injected intravenously in order to reach target tissues. However, it is known that they can be rapidly removed from blood circulation by the immune system. CDDS are removed via the complement system and via the cells of the mononuclear phagocyte system (MPS), after their recognition by opsonins and/or receptors present at the cell surface. This recognition is dependent on the physicochemical characteristics of the CDDS. In this study, we will focus on parameters influencing the interactions of opsonins and the macrophage plasma membrane with the surface of CDDS, whereby parameters of the polymer coating become necessary to provide good protection.
Assuntos
Coloides/administração & dosagem , Sistemas de Liberação de Medicamentos , Animais , Coloides/farmacocinética , Proteínas do Sistema Complemento/fisiologia , Humanos , Lipossomos/administração & dosagem , Lipossomos/farmacocinética , Macrófagos/fisiologia , NanoestruturasRESUMO
Lipid nanocapsules (LNCs) containing poly(ethylene glycol) (PEG) were developed according to a phase inversion process without organic solvent. The distribution of PEG chains at the surface was determined due to electrokinetic properties, in order to correlate it with protein adsorption potentiality. In this aim, electrophoretic mobilities were measured as a function of ionic strength and pH, for particles differing by their size, dialysis effects, and the presence or not of lecithin in their shell. The study allowed the determination of the isoelectric point (pI) as well as the charge density (ZN) in relation with the dipolar distribution in the polyelectrolyte accessible layer (depth = 1/lambda), by using soft-particle electrophoresis analysis. These parameters pointed out that the PEG surface organization was dependent on the particle size. Moreover, this organization could be modified by dialyzing particles and/or by formulating them with or without lecithin. Lecithin was found to be present in the inner part of the polyelectrolyte layer and to play a role in the outer part disorganization. Dialyzing LNCs formulated with lecithin allowed to obtain stable and well-structured nanocapsules, ready to an in vivo use as drug delivery system.