RESUMO
AIM & METHODS: The aim of the present work was to encapsulate paclitaxel (Ptx) in various lipid nanocapsules (LNCs) formulations and then to compare their pharmacokinetics and efficacy on a subcutaneous isograft model in rats. RESULTS: Three different Ptx formulations were obtained. Drug payloads ranged from 1.32 to 3.62 mg Ptx/g of formulation. After oral administration the area under concentration-time curve was higher (p < 0.05) if Ptx was encapsulated, (1,2 Distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(PEG)] (DSPE-PEG-NH2)) LNCs displaying the highest area under concentration-time curve (p < 0.05). Efficacy was better than control for standard LNCs after oral administration (p < 0.05) and for (DSPE-PEG-NH2) LNCs after intravenous administration. Despite good absorption, (DSPE-PEG-NH2) LNCs failed to remain efficient after oral route. CONCLUSION: This study highlights the importance of efficacy studies paired to pharmacokinetic studies for nanomedicines.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Glioma/tratamento farmacológico , Nanocápsulas/química , Paclitaxel/administração & dosagem , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Administração Oral , Aminação , Animais , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular , Feminino , Glioma/patologia , Humanos , Injeções Intravenosas , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Ratos , Ratos Endogâmicos F344RESUMO
Physicochemical coating properties are often considered to be determining factors for in vivo characteristics of superparamagnetic iron oxide nanoparticles, used as contrast agent in Magnetic Resonance Imaging (MRI). To investigate the electrical charge (modified by zero, one or two ammonium groups) and the molecule length (3, 5 or 7 methylene chains) effects of bisphosphonate-type coatings, we assessed the complement activation, in vivo plasma and tissue relaxation time alterations of intravenously injected small iron oxide nanoparticles (<25 nm) on male healthy Wistar rats. The presence of ammonium groups induces a weak activation of the complement whatever the size and the concentration of particles, whereas hydroxyethylenebisphosphonate (HEBP)-coated particles are poor complement activators only at the lowest concentration. In vivo, HEBP-coated nanoparticles have the greatest prolonged relaxation time effects, despite their higher negative electrical charge, contrary to two ammonium bearing coatings. No significant differences were observed between mono-ammonium molecular coatings.
Assuntos
Difosfonatos/administração & dosagem , Compostos Férricos/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Compostos de Amônio/química , Animais , Ativação do Complemento/efeitos dos fármacos , Difosfonatos/química , Eletroquímica , Compostos Férricos/química , Coração/efeitos dos fármacos , Coração/fisiologia , Rim/efeitos dos fármacos , Rim/fisiologia , Fígado/efeitos dos fármacos , Fígado/fisiologia , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Fenômenos Magnéticos , Masculino , Nanopartículas Metálicas/química , Ratos , Ratos Wistar , Baço/efeitos dos fármacos , Baço/fisiologiaRESUMO
The aim of this work was to elucidate the impact of polyethylene glycol (PEG) polymeric coating on the in vitro and in vivo stealthiness of magnetic nanocarriers loaded or not with the anticancer drug doxorubicin. The comparison was made between aqueous suspensions of superparamagnetic iron oxide nanoparticles (SPIONs) stabilized by either citrate ions (C-SPIONs) or PEG(5000) (P-SPIONs), the latter being loaded or not with doxorubicin via the formation of a DOX-Fe(2+) complex (DLP-SPIONs). After determination of their relevant physico-chemical properties (size and surface charge), nanoparticle (NP) stealthiness was studied in vitro (ability to activate the complement system and uptake by monocytes and macrophage-like cells) and in vivo in mice (blood half-life; t(1/2), and biodistribution in main clearance organs). These aspects were quantitatively assessed by atomic absorption spectrometry (AAS). Complement activation dramatically decreased for sterically stabilized P-SPIONs and DLP-SPIONs in comparison with C-SPIONs stabilized by charge repulsion. Monocyte and macrophage uptake was also largely reduced for pegylated formulations loaded or not with doxorubicin. The t(1/2) in blood for P-SPIONs was estimated to be 76 ± 6 min, with an elimination mainly directed to liver and spleen. Thanks to their small size (<80 nm) and a neutral hydrophilic polymer-extended surface, P-SPIONs exhibit prolonged blood circulation and thus potentially an increased level in tumor delivery suitable for magnetic drug targeting applications.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Nanopartículas de Magnetita/química , Polietilenoglicóis/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Citratos , Ativação do Complemento/efeitos dos fármacos , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Feminino , Meia-Vida , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Monócitos/metabolismo , Tamanho da Partícula , Espectrofotometria Atômica , Baço/metabolismo , Fatores de Tempo , Distribuição TecidualRESUMO
Evaluation of the biocompatibility of pH-triggered targeting micelles was performed with the goal of studying the effect of a poly(ethylene oxide) (PEO) coating on micelle stealth properties. Upon protonation under acidic conditions, pH-sensitive poly(2-vinylpyridine) (P2VP) blocks were stretched, exhibiting positive charges at the periphery of the micelles as well as being a model targeting unit. The polymer micelles were based on two different macromolecular architectures, an ABC miktoarm star terpolymer and an ABC linear triblock copolymer, which combined three different polymer blocks, i.e. hydrophobic poly(ε-caprolactone), PEO and P2VP. Neutral polymer micelles were formed at physiological pH. These systems were tested for their ability to avoid macrophage uptake, their complement activation and their pharmacological behavior after systemic injection in mice, as a function of their conformation (neutral or protonated). After protonation, complement activation and macrophage uptake were up to twofold higher than for neutral systems. By contrast, when P2VP blocks and the targeting unit were buried by the PEO shell at physiological pH, micelle stealth properties were improved, allowing their future systemic injection with an expected long circulation in blood. Smart systems responsive to pH were thus developed which therefore hold great promise for targeted drug delivery to an acidic tumoral environment.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Micelas , Polietilenoglicóis/química , Animais , Linhagem Celular , Fenômenos Químicos/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Fluorescência , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Injeções Intravenosas , Cinética , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Rodaminas/metabolismoRESUMO
OBJECTIVE: Volumetric evaluation of the myocardial viability post-infarction in rats using 3D in vivo MR imaging at 7 T using injection of an extracellular paramagnetic contrast agent and intravascular superparamagnetic iron oxide nanoparticles in the same imaging session. MATERIALS AND METHODS: Five hours after induction of permanent myocardial infarction in rats (n=6), 3D in vivo T1- and T2-weighted MR Imaging was performed prior to and after Gd-DOTA injection (0.2 mmol/kg) and prior to and after nanoparticle injection (5 mg Fe/kg) to assess infarct size and myocardial viability. RESULTS: 3D MR Imaging using a successive contrast agent injection showed a difference of infarct size after Gd-DOTA injection on T1-weighted images compared to the one measured on T2-weighted images after Gd-DOTA and nanoparticle injection. CONCLUSION: The use of 3D T1- and T2-weighted MR Imaging using a double contrast agents protocol made possible the accurate characterization of myocardial infarction volume and allowed the detection of myocardial viability post-infarction in rats.
Assuntos
Meios de Contraste , Compostos Heterocíclicos , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Infarto do Miocárdio/patologia , Compostos Organometálicos , Análise de Variância , Animais , Infarto do Miocárdio/terapia , Nanotecnologia , Tamanho da Partícula , RatosRESUMO
Mycobacterium ulcerans is an environmental pathogen concerning mainly the tropical countries; it is the causative agent of Buruli ulcer, which has become the third most important mycobacterial disease. In spite of water-linked epidemiological studies to identify the sources of M. ulcerans, the reservoir and the mode of transmission of this organism remain elusive. To determine the ecology and the mode of transmission of M. ulcerans we have set up an experimental model. This experimental model demonstrated that water bugs were able to transmit M. ulcerans by bites. In insects, the bacilli were localized exclusively within salivary glands, where it could both multiply contrary to other mycobacteria species. In another experimental study, we report that the crude extracts from aquatic plants stimulate in vitro the growth of M. ulcerans as much as the biofilm formation by M. ulcerans has been observed on aquatic plants. Given that the water bugs are essentially carnivorous, it is difficult to imagine a direct contact in the contamination of aquatic bugs and plants. It seems very likely that an intermediate host exists. In an endemic area of Daloa in Côte d'Ivoire, our observations were confirmed.
Assuntos
Infecções por Mycobacterium não Tuberculosas/transmissão , Mycobacterium ulcerans , Animais , Ecossistema , Humanos , Insetos/microbiologia , Mycobacterium ulcerans/crescimento & desenvolvimento , Mycobacterium ulcerans/isolamento & purificaçãoRESUMO
RATIONALE AND OBJECTIVES: The purpose of this study was to evaluate superparamagnetic iron oxide (SPIO) nanoparticles to discriminate infarcted from normal tissue after myocardial infarction using high field MR imaging (7 tesla). MATERIALS AND METHODS: Permanent myocardial infarction was induced in rats. SPIO nanoparticles (1 mg Fe/kg) were assessed with T1-weighted gradient echo sequence to visualize the myocardial infarction 48 hours after ligature (n = 6). Furthermore, MR Imaging was performed using a T2-weighted RARE sequence and nanoparticles were injected (5 or 10 mg Fe/kg) on 36 rats 5, 24 or 48 hours after infarction. RESULTS: No changes in contrast between normal and infarcted myocardium was observed after nanoparticle injection on T1-weighted images. However, nanoparticles induced a significant contrast increase between normal and infarcted myocardium on T2-weighted images whatever the delay between infarction and imaging (2.99 +/- 1.66 preinjection vs. 7.82 +/- 1.96 after SPIO injection at a dose of 5 mg Fe/kg 5 hours postinfarction, P = 0.0001). CONCLUSIONS: Nanoparticle injection made it possible to discriminate normal from infarcted myocardium on T2-weighted images. However, the high magnetic field prevented the visualization of the T1 effect of SPIO nanoparticles.