RESUMO
Glioblastoma remains a cancer for which the effectiveness of treatments has shown little improvement over the last decades. For this pathology, multiple therapies combining resection, chemotherapy and radiotherapy remain the norm. In this context, the use of high-Z nanoparticles such as gold or hafnium to potentiate radiotherapy is attracting more and more attention. Here, we evaluate the potentiating effect of hollow shells made of gold and iron oxide nanoparticles (hybridosomes®) on the radiotherapy of glioblastoma, using murine GL261-Luc+ brain tumor model. While iron oxide seems to have no beneficial effect for radiotherapy, we observe a real effect of gold nanoparticles-despite their low amount-with a median survival increase of almost 20% compared to radiotherapy only and even 33% compared to the control group. Cellular and in vivo studies show that a molecule of interest nano-precipitated in the core of the hybridosomes® is released and internalized by the surrounding brain cells. Finally, in vivo studies show that hybridosomes® injected intra-tumorally are still present in the vicinity of the brain tumor more than 5â¯days after injection (duration of the Stupp protocol's radiation treatment). Interestingly, one mouse treated with radiotherapy in the presence of gold-containing hybridosomes® survived 78â¯days. Monitoring of the tumoral growth of this long-term survivor using both MRI and bioluminescence revealed a decrease of the tumor size after treatment. These very encouraging results are a proof-of-concept that hybridosomes® are really effective tools for the development of combined therapies (chemo-radiotherapy).
Assuntos
Neoplasias Encefálicas , Glioblastoma , Nanopartículas Metálicas , Nanocápsulas , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Camundongos , Nanocápsulas/uso terapêuticoRESUMO
Drug nanocapsules coated with iron oxide nanoparticles (SPION) were elaborated by the simultaneous nanoprecipitation of the drug and the nanoparticles, through solvent shifting. We examined four drugs: sorafenib, sorafenib tosylate, α-tocopherol and paclitaxel, to cover the cases of molecular solids, ionic solids, and molecular liquids. We first investigated the formation of the drug core in the final mixture of solvents at different concentrations. A Surfactant-Free Micro-Emulsion domain (SFME, thermodynamically stable) was observed at low drug concentration and an Ouzo domain (metastable) at high drug concentration, except for the case of paclitaxel which crystallizes at high concentration without forming an Ouzo domain. When co-nanoprecipitated with the molecular drugs in the Ouzo domain (sorafenib or α-tocopherol), the SPION limited the coalescence of the drug particles to less than 100 nm, forming capsules with a drug encapsulation efficiency of ca 80 %. In contrast, larger capsules were formed from the SFME or when using the ionic form (sorafenib tosylate). Finally, the sorafenib-SPION capsules exhibit a similar chemotherapeutic effect as the free drug on the hepatocellular carcinoma in vitro.
Assuntos
Neoplasias Hepáticas , Nanocápsulas , Humanos , Nanocápsulas/química , Solventes , Sorafenibe , alfa-Tocoferol , Estrutura Molecular , Paclitaxel , Nanopartículas Magnéticas de Óxido de FerroRESUMO
HYPOTHESIS: Ternary systems made of water, a water-miscible solvent, and hydrophobic solutes spontaneously produce metastable particles by the "Ouzo effect" and thermodynamically stable "Surfactant-Free Micro Emulsions" (SFME). However, the use of different analyses has led to a variability in the criteria to determine the boundaries of the Ouzo domain. We hypothesized that this could be clarified by investigating the stability and the physical state of the particles. EXPERIMENTS: We investigate four systems using both solid and liquid solutes and two different solvents, and achieved a careful investigation of their phase diagrams, using DLS, Nanoparticle Tracking Analysis, NMR, Multiple Light Scattering, electrophoretic mobility, and fluorescence analysis. FINDINGS: Our results evidence that the transition from the monophasic to the Ouzo domains does not coincide with the cloudiness curve, and that compositions in the Ouzo domain can look fully transparent, in contrast to what is often considered. This transition is best determined by stability analysis. The cloudiness curve corresponds to the formation of particles with a large size dispersity. In the Ouzo domain, we observed an exchange of solute between the continuous phase and solute particles swollen with solvent. In addition, the particles are stabilized against coalescence by their high negative charge.
Assuntos
Tensoativos , Água , Solventes/química , Água/química , Emulsões/química , SoluçõesRESUMO
Particles stabilize fluid interfaces. In particular, oil/water Pickering emulsions undergo limited coalescence, yielding droplets of smaller size as the amount of particles is increased. Herein, we studied the effect of hydrophobic nanoparticles (<10 nm, alkyl-coated) on submicronic droplets (ca 100 nm) formed in an Ouzo system. We investigated thoroughly the water/tetrahydrofuran (THF)/butylated hydroxytoluene (BHT) reference diagram, in the absence and in the presence of nanoparticles, using the Nanoparticle Tracking Analysis (NTA) technique. This allowed us to characterize the size distributions in a much finer way than what is usually obtained using conventional Dynamic Light Scattering (DLS). Both a Surfactant-Free Microemulsion (SFME, thermodynamically stable) and an Ouzo (metastable spontaneous emulsion) domains were identified and the transition from one to the other could be characterized by specific features of the droplet size distributions. We found that the presence of the nanoparticles limits coalescence in the metastable domain. We also show that the alkyl-coated nanoparticles are irreversibly attached to the liquid-liquid interface.
RESUMO
We investigate the encapsulation in hybridosomes®, a type of capsules unique regarding their structure and method of elaboration. Hybridosomes® are made of a single shell of inorganic nanoparticles (~5 nm) crosslinked with a polymer and are easily obtained via spontaneous emulsification in a ternary mixture THF/water/butylated hydroxytoluene (BHT). Our main finding is that an exceptionally high concentration of a hydrophobic model dye can be loaded in the hybridosomes®, up to 0.35 mol.L-1 or equivalently 170 g.L-1 or 450,000 molecules/capsule. The detailed investigation of the encapsulation mechanism shows that the dye concentrates in the droplets during the emulsification step simultaneously with capsule formation. Then it precipitates inside the capsules during the course of solvent evaporation. In vitro fluorescence measurements show that the nano-precipitated cargo can be transferred from the core of the hybridosomes® to the membrane of liposomes. In vivo studies suggest that the dye diffuses through the body during several days. The released dye tends to accumulate in body-fat, while the inorganic nanoparticles remain trapped into the liver and the spleen macrophages.