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PURPOSE: This study aims at evaluating the non-invasive Magnetic Resonance Imaging (MRI) technic to visualize a synthetic composite hernia mesh using a rodent model and to document the integration of this device over 4 months. METHODS: Uncoated polyethylene terephthalate mesh and synthetic composite mesh-faced on the visceral side with a chemically engineered layer of copolymer of glycolide, caprolactone, trimethylene carbonate, and lactide to minimize tissue attachment-were placed intraperitoneally in rats, facing the caecum previously scraped to promote petechial bleeding and subsequent adhesions. Meshes fate follow-up was performed 4, 10, and 16-weeks post-implantation using a rodent dedicated high field MRI. Magnetization transfer (MT) images were acquired, associated with pneumoperitonealMRI performed after intraperitoneal injection of 8 mL gas to induce mechanical stress on the abdominal wall. RESULTS: Uncoated meshes were clearly visible using both T2-weighted and MT imaging during the whole study while composite meshes conspicuity was not so evident on T2-weighted MRI and could be improved using MT imaging. Adhesions and collagen infiltration were massive for the uncoated meshes as expected. On the contrary, composite meshes showed very limited adhesion, and, if any, occurring at the edge of the mesh, starting at the fixation points. CONCLUSIONS: Magnetization transfer imaging allows to detect mesh integration and, associated with pneumoperitoneum, was able to probe the effective minimizing effect of the synthetic polymeric barrier on visceral attachments. However, magnetization transfer imaging could not unambiguously allow the visualization of the mesh through the polymeric barrier.
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Hérnia Ventral , Ratos , Animais , Hérnia Ventral/cirurgia , Telas Cirúrgicas , Projetos Piloto , Polietilenotereftalatos , Seguimentos , Aderências Teciduais/patologia , Imageamento por Ressonância Magnética/métodos , ColágenoRESUMO
PURPOSE: To propose a method for determining tissue oxygenation via the measurement of fat T1 . The method is based on a 2D fat/water chemical shift-encoded and T1 -weighted acquisition. THEORY AND METHODS: A 2D data set was acquired with a fast spin echo sequence with several echo asymmetries and repetition times, wherein one dimension is related to the fat/water phase modulation and the other to the T1 saturation recovery. A joint magnitude-based process of phase modulation and T1 evolution allowed for the collection of the fat fraction and T1 maps with resolved fat or water dominance ambiguity while avoiding the phased error problem. RESULTS: In vitro imaging allowed for the attribution of fat content for different water/oil emulsions that demonstrated longitudinal relaxation rate (R1 ) sensitivity to the oxygenated emulsion environment. The fat R1 values were subsequently compared to reference values, which were measured using low receiver bandwidth acquisition to enhance water and fat signal separations. In vivo feasibility of tissue oxygenation assessment was demonstrated by investigating interscapular brown adipose tissue modifications during an air/carbogen challenge in rats. CONCLUSION: The proposed method offers a precise and robust estimate of tissue oxygenation illustrated by the method's ability to detect-brown adipose tissue oxygenation modifications. Magn Reson Med 79:1981-1991, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
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Tecido Adiposo Marrom/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Oxigênio/química , Animais , Dióxido de Carbono/química , Feminino , Análise dos Mínimos Quadrados , Modelos Estatísticos , Imagens de Fantasmas , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , ÁguaRESUMO
Internal radiation strategies hold great promise for glioblastoma (GB) therapy. We previously developed a nanovectorized radiotherapy that consists of lipid nanocapsules loaded with a lipophilic complex of Rhenium-188 (LNC188Re-SSS). This approach resulted in an 83 % cure rate in the 9L rat glioma model, showing great promise. The efficacy of LNC188Re-SSS treatment was optimized through the induction of a T-cell immune response in this model, as it is highly immunogenic. However, this is not representative of the human situation where T-cell suppression is usually encountered in GB patients. Thus, in this study, we investigated the efficacy of LNC188Re-SSS in a human GB model implanted in T-cell deficient nude mice. We also analyzed the distribution and tissue retention of LNC188Re-SSS. We observed that intratumoral infusion of LNCs by CED led to their complete distribution throughout the tumor and peritumoral space without leakage into the contralateral hemisphere except when large volumes were used. Seventy percent of the 188Re-SSS activity was present in the tumor region 24 h after LNC188Re-SSS injection and no toxicity was observed in the healthy brain. Double fractionated internal radiotherapy with LNC188Re-SSS triggered survival responses in the immunocompromised human GB model with a cure rate of 50 %, which was not observed with external radiotherapy. In conclusion, LNC188Re-SSS can induce long-term survival in an immunosuppressive environment, highlighting its potential for GB therapy.
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Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Nanocápsulas/uso terapêutico , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Rênio/uso terapêutico , Animais , Autorradiografia , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Nus , Nanocápsulas/administração & dosagem , Radioisótopos/administração & dosagem , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Rênio/administração & dosagem , Rênio/farmacocinética , Linfócitos T/patologia , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma (GB) displays diffusely infiltrative growth patterns. Dispersive cells escape surgical resection and contribute to tumour recurrence within a few centimeters of the resection cavity in 90% of cases. We know that the non-neoplastic stromal compartment, in addition to infiltrative tumour cells, plays an active role in tumour recurrence. We isolated a new stromal cell population from the histologically normal surgical margins of GB by computer-guided stereotaxic biopsies and primary culture. These GB-associated stromal cells (GASCs) share phenotypic and functional properties with the cancer-associated fibroblasts (CAFs) described in the stroma of carcinomas. In particular, GASCs have tumour-promoting effects on glioma cells in vitro and in vivo. Here, we describe a quantitative proteomic analysis, using iTRAQ labelling and mass spectrometry, to compare GASCs with control stromal cells derived from non-GB peripheral brain tissues. A total of 1077 proteins were quantified and 67 proteins were found to differ between GASCs and control stromal cells. Several proteins changed in GASCs are related to a highly motile myofibroblast phenotype, and to wound healing and angiogenesis. The results for several selected proteins were validated by western blotting or flow cytometry. Furthermore, the effect of GASCs on angiogenesis was confirmed using the orthotopic U87MG glioma model. In conclusion, GASCs, isolated from GB histologically normal surgical margins and found mostly near blood vessels, could be a vascular niche constituent establishing a permissive environment, facilitating angiogenesis and possibly colonization of recurrence-initiating cells. We identify various proteins as being expressed in GASCs: some of these proteins may serve as prognostic factors for GB and/or targets for anti-glioma treatment.
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Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Miofibroblastos/patologia , Neovascularização Patológica , Células Estromais/patologia , Biomarcadores Tumorais/metabolismo , Biópsia , Western Blotting , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/cirurgia , Comunicação Celular , Separação Celular , Quimiocina CXCL12/metabolismo , Técnicas de Cocultura , Citometria de Fluxo , Glioblastoma/metabolismo , Glioblastoma/cirurgia , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Miofibroblastos/metabolismo , Neoplasia Residual , Fenótipo , Cultura Primária de Células , Proteômica/métodos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Células Estromais/metabolismo , Espectrometria de Massas em Tandem , Células Tumorais Cultivadas , CicatrizaçãoRESUMO
BACKGROUND: Intraperitoneal mesh implantation is often associated with formation of adhesion to the mesh. This experimental study examines the potential of minimally invasive pneumoperitoneal-MRI to assess these adhesions in a preclinical context. METHODS: Uncoated polyethylene terephthalate meshes were placed intraperitoneally in rats, in regard to the caecum previously scraped to promote petechial bleeding and subsequent adhesions. Examinations were performed 2-weeks post mesh implantation using a rodent dedicated high field MRI. Respiratory-triggered T2-weighted images were acquired prior to and after intraperitoneal injection of ~8-10 mL gas to induce a mechanical stress on the abdominal wall. RESULTS: Adhesions are occasionally seen in sham-operated rats as opposed to rats receiving polyethylene terephthalate meshes. On high-resolution images, meshes can be detected due to their characteristic net shape. However, evidence of adherence is only found if intraperitoneal gas injection is performed, when a ~1-cm elevation of the abdominal wall is observed. When adherence occurs between the mesh and the caecum, the latter remains in contact with the wall. Looser adherences between visceral tissue and meshes are also observed. CONCLUSIONS: T2-weighted pneumoperitoneal-MRI is a powerful tool for assessing adherence after intraperitoneal mesh implantation. According to the mini-invasive procedure adopted here, this approach may allow a temporal follow-up of adherence fate.
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Doenças do Ceco/patologia , Imageamento por Ressonância Magnética/métodos , Peritônio/cirurgia , Pneumoperitônio Artificial , Telas Cirúrgicas/efeitos adversos , Aderências Teciduais/patologia , Animais , Doenças do Ceco/etiologia , Ceco/cirurgia , Feminino , Polietilenotereftalatos , Polímeros , Ratos Sprague-Dawley , Aderências Teciduais/etiologiaRESUMO
PURPOSE: The feasibility of noninvasive visualization of composite meshes used in ventral hernia repair by amide-proton transfer magnetic resonance imaging (APT-MRI) was explored. METHODS: Magnetization transfer asymmetry ratio images of composite meshes were obtained in vitro and in vivo from fast-spin echo acquisitions with frequency saturation offsets of ±3.5 ppm with respect to water frequency and no saturation. Three rats were assessed with APT-MRI each week for 1 month after the intraperitoneal implantation of two meshes, one on each side of the incision. One mesh was coated with collagen and the other was not. RESULTS: In vitro, meshes were delineated with APT-MRI as a thin continuous linear hypersignal located on one side of the mesh. Unlike collagen-free meshes, collagen-coated meshes were easily identified in vivo with APT-MRI during the first 3 weeks postimplantation. The composite meshes magnetization transfer asymmetry ratio (8.7 ± 2.8%) were significantly different from the muscle magnetization transfer asymmetry ratio value (-0.9 ± 1.6%). After a month, the mesh value dropped down to 1.1 ± 3.9%. Muscle and mesh magnetization transfer asymmetry ratio values were not significantly different and mesh conspicuity was no longer possible. CONCLUSION: The results suggest that APT-MRI is a promising technique for noninvasive, early postsurgical visualization of composite meshes used in ventral hernia repair.
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Hérnia Ventral/diagnóstico , Hérnia Ventral/cirurgia , Herniorrafia/instrumentação , Imageamento por Ressonância Magnética/métodos , Telas Cirúrgicas , Amidas/análise , Animais , Materiais Revestidos Biocompatíveis/análise , Feminino , Aumento da Imagem/métodos , Masculino , Prótons , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
Hydrophobic macromolecular contrast agents (MMCAs) are highly desirable to provide safe and efficient magnetic resonance (MR) visibility to implantable medical devices. In this study, we report on the synthesis and evaluation of novel biodegradable poly(ε-caprolactone)-based MMCAs. Poly(α-propargyl-ε-caprolactone-co-ε-caprolactone)s containing 2, 5, and 10 mol % of propargyl groups have been prepared by ring-opening copolymerization of ε-caprolactone and the corresponding propargylated lactone. In parallel, a diazido derivative of the clinically used diethylenetriaminepentaacetic acid (DTPA)/Gd(3+) complex has been synthesized. Finally, MRI-visible poly(ε-caprolactone)s (PCLs) were obtained by the efficient click ligation of these compounds via a Cu(I)-catalyzed [3 + 2] cycloaddition. ICP-MS analyses confirmed the efficient coupling of the complex on the PCL backbone with the MRI-visible PCLs containing 1.0, 2.6, and 3.6 wt % of Gd(3+). The influence of the Gd(3+) grafting density on the T1 relaxation times and on the MRI visibility of the novel biodegradable MMCAs was evaluated. Finally, their stability and cytocompatibility were assessed with regard to their potential as innovative MRI-visible biomaterials for biomedical applications.
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Materiais Biocompatíveis , Meios de Contraste , Gadolínio DTPA , Imageamento por Ressonância Magnética , Poliésteres , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Proliferação de Células , Meios de Contraste/química , Meios de Contraste/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Gadolínio DTPA/química , Gadolínio DTPA/metabolismo , Substâncias Macromoleculares/química , Substâncias Macromoleculares/metabolismo , Camundongos , Estrutura Molecular , Poliésteres/química , Poliésteres/metabolismoRESUMO
Nuclear Magnetic Resonance (NMR) based diffusion methods open new perspectives for nanomedicine characterization and their bioenvironment interaction understanding. This review summarizes the theoretical background of diffusion phenomena. Self-diffusion and mutual diffusion coefficient notions are featured. Principles, advantages, drawbacks, and key challenges of NMR diffusometry spectroscopic and imaging methods are presented. This review article also gives an overview of representative applicative works to the nanomedicine field that can contribute to elucidate important issues. Examples of in vitro characterizations such as identification of formulated species, process monitoring, drug release follow-up, nanomedicine interactions with biological barriers are presented as well as possible transpositions for studying in vivo nanomedicine fate.
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Imageamento por Ressonância Magnética , Nanomedicina , Difusão , Imagem de Difusão por Ressonância Magnética , Espectroscopia de Ressonância MagnéticaRESUMO
Glioma is a type of cancer with a very poor prognosis with a survival of around 15 months in the case of glioblastoma multiforme (GBM). In order to advance in personalized medicine, we developed polymeric nanoparticles (PNP) loaded with both SPION (superparamagnetic iron oxide nanoparticles) and doxorubicin (DOX). The former being used for its potential to accumulate the PNP in the tumor under a strong magnetic field and the later for its therapeutic potential. The emulsion solvent and evaporation method was selected to develop monodisperse PNP with high loading efficiency in both SPION and DOX. Once injected in mice, a significant accumulation of the PNP was observed within the tumoral tissue under static magnetic field as observed by MRI leading to a reduction of tumor growth rate.
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Glioblastoma , Nanopartículas de Magnetita , Animais , Linhagem Celular Tumoral , Doxorrubicina , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Nanopartículas Magnéticas de Óxido de Ferro , Camundongos , Tamanho da Partícula , Medicina de PrecisãoRESUMO
There is a growing interest in magnetic nanocomposites in biomaterials science. In particular, nanocomposites that combine poly(lactide) (PLA) nanofibers and superparamagnetic iron oxide nanoparticles (SPIONs), which can be obtained by either electrospinning of a SPION suspension in PLA or by precipitating SPIONs at the surface of PLA, are well documented in the literature. However, these two classical processes yield nanocomposites with altered materials properties, and their long-term in vivo fate and performances have in most cases only been evaluated over short periods of time. Recently, we reported a new strategy to prepare well-defined PLA@SPION nanofibers with a quasi-monolayer of SPIONs anchored at the surface of PLA electrospun fibers. Herein, we report on a 6-month in vivo rat implantation study with the aim of evaluating the long-term magnetic resonance imaging (MRI) properties of this new class of magnetic nanocomposites, as well as their tissue integration and degradation. Using clinically relevant T2-weighted MRI conditions, we show that the PLA@SPION nanocomposites are clearly visible up to 6 months. We also evaluate here by histological analyses the slow degradation of the PLA@SPIONs, as well as their biocompatibility. Overall, these results make these nanocomposites attractive for the development of magnetic biomaterials for biomedical applications.
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Nanopartículas de Magnetita , Nanocompostos , Animais , Nanopartículas Magnéticas de Óxido de Ferro , Imageamento por Ressonância Magnética , Poliésteres , RatosRESUMO
In recent years, the use of quantum dots (Qdots) to obtain biological images has attracted attention due to their excellent luminescent properties and the possibility of their association with contrast agents for magnetic resonance imaging (MRI). In this study, Gd3+/ZnO (ZnOGd) were conjugated with Qdots composed of a gadolinium-copper-indium-sulphur core covered with a ZnS shell (GCIS/ZnS Qdots). This conjugation is an innovation that has not yet been described in the literature, and which aims to improve Qdot photoluminescent properties. Structural and morphological Qdots features were obtained by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermogravimetric analyses (TGA). The photoluminescent properties were examined by emission (PL) and excitation (PLE) spectra. A new ZnOGd and GCIS/ZnS (ZnOGd-GCIS/ZnS) nanomaterial was synthesized with tunable optical properties depending on the ratio between the two native Qdots. A hydrophilic or lipophilic coating, using 3-glycidyloxypropyltrimethoxysilane (GPTMS) or hexadecyltrimethoxysilane (HTMS) on the surface of ZnOGd-GCIS/ZnS Qdots, was carried out before assessing their efficiency as magnetic resonance contrast agents. ZnOGd-GCIS/ZnS had excellent luminescence and MRI properties. The new Qdots developed ZnOGd-GCIS/ZnS, mostly constituted of ZnOGd (75%), which had less cytotoxicity when compared to ZnOGd, as well as greater cellular uptake.
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INTRODUCTION: The aim of this work was to map E-selectin expression in a traumatic brain injury model using a newly-designed MR contrast agent. Iron cores, responsible for susceptibility effects and therefore used as T2* contrast agents, need to be coated in order to be stabilized and need to be targeted to be useful. METHODS: We have designed a molecule coating composed, at one end, of bisphosphonate to ensure anchorage of the coating on the iron core and, at the other end, of Fukuda's defined heptapeptide known to target selectin binding sites. CONCLUSION: The synthesized nanoparticles were able to non-invasively target the traumatic brain lesion, inducing a specific T2* decrease of about 25% up to at least 70 min post-injection of the targeted contrast agent.
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Lesões Encefálicas/metabolismo , Meios de Contraste , Selectina E/metabolismo , Ferro , Óxidos , Animais , Lesões Encefálicas/diagnóstico por imagem , Lesões Encefálicas/patologia , Meios de Contraste/química , Dextranos , Difosfonatos/química , Feminino , Óxido Ferroso-Férrico , Nanopartículas de Magnetita , Nanopartículas , Oligopeptídeos/química , Polietilenoglicóis/química , Cintilografia , Ratos , Ratos Sprague-Dawley , TecnécioRESUMO
Oxygen is essential in physiology and pathophysiology. Electron paramagnetic resonance (EPR) oximetry, using oxygen sensitive paramagnetic materials, could be attractive for measuring oxygen in tissues. The aim of the present study was to assess the properties of lipid nanocapsules (LNCs) loaded with the nitroxide tempo-benzoate (TB) or tetrathiatriarylmethyl (TAM) radicals. LNCs loaded with the EPR probes were successfully prepared by the phase inversion process leading to nanocapsules of about 60â¯nm. LNCs protected the TB radical against reduction in vitro. The calibration of the EPR line width (LW) as a function of the pO2 showed a two-fold increase in sensitivity with TAM-LNC compared to hydrophilic trityl radical. The TAM-LNCs were evaluated in vivo. Contrarily to unencapsulated TAM, for which a rapid decrease in EPR signal was observed, the half-life of TAM-LNCs administered in muscles or in tumours exceeded an hour. Carbogen-challenges in mice demonstrated that the TAM-LNCs responded well to changes in oxygen environment. However, the apparent pO2 values acquired were higher than the expected physiological values. These results warrant further investigation in the formulation of stable nano-objects encapsulating EPR oxygen sensitive probes.
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Espectroscopia de Ressonância de Spin Eletrônica/métodos , Nanocápsulas , Oximetria/métodos , Oxigênio/metabolismo , Animais , Benzoatos/química , Dióxido de Carbono/metabolismo , Química Farmacêutica/métodos , Meia-Vida , Lipídeos/química , Masculino , Camundongos , Camundongos Endogâmicos C3H , Compostos de Tritil/químicaRESUMO
Hypoxia is common occurrence of the tumour microenvironment, wherein heterogeneous gradients of O2 give rise to tumoural cells which are highly malignant, metastatic, and resistant to therapeutic efforts. Thus, the assessment and imaging of hypoxia is essential for tumour diagnosis and treatment. Magnetic resonance imaging and, more specifically, the quantitative assessment of longitudinal relaxation time enhancement, was shown to enable the mapping of oxygen in tumours with increased sensitivity for lipids as compared to water signal. Unfortunately, this can only be applied to tumours with high lipid content. To overcome this issue, we propose the use of lipid nanocapsules (LNCs). LNCs have been demonstrated as excellent core-shell nanocarriers, wherein the lipidic-core is used for lipophilic drug encapsulation, enabling treatment of highly malignant tumours. Herein, however, we exploited the lipidic-core of the LNCs to develop a simple but effective technique to increase the lipidic content within tissues to enable the assessment and mapping of pO2. LNCs were prepared using the phase-inversion technique to produce 60â¯nm sized nanoparticles, and in vitro studies demonstrated the permeability and responsiveness of LNCs to O2. To evaluate the ability of LNCs to respond to changes in pO2in vivo, after a hyperoxic challenge, three animal models, namely a normal tissue model (gastrocnemius muscle tissue) and two tumour tissue models (subcutaneous fibrosarcoma and intracerebral glioblastoma) were explored. LNCs were found to be responsive to variation of O2in vivo. Moreover, the use of MRI enabled the mapping of oxygen gradients and heterogeneity within tumours.
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Lipídeos/química , Imageamento por Ressonância Magnética , Nanocápsulas/química , Oxigênio/análise , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/patologia , Masculino , Camundongos , Pressão Parcial , Ratos Sprague-Dawley , Reprodutibilidade dos TestesRESUMO
Noninvasive diagnostic by imaging combined with a contrast agent (CA) is by now the most used technique to get insight into human bodies. X-ray and magnetic resonance imaging (MRI) are widely used technologies providing complementary results. Nowadays, it seems clear that bimodal CAs could be an emerging approach to increase the patient compliance, accessing different imaging modalities with a single CA injection. Owing to versatile designs, targeting properties, and high payload capacity, nanocarriers are considered as a viable solution to reach this goal. In this study, we investigated efficient superparamagnetic iron oxide nanoparticle (SPION)-loaded iodinated nano-emulsions (NEs) as dual modal injectable CAs for X-ray imaging and MRI. The strength of this new CA lies not only in its dual modal contrasting properties and biocompatibility, but also in the simplicity of the nanoparticulate assembling: iodinated oily core was synthesized by the triiodo-benzene group grafting on vitamin E (41.7% of iodine) via esterification, and SPIONs were produced by thermal decomposition during 2, 4, and 6 h to generate SPIONs with different morphologies and magnetic properties. SPIONs with most anisotropic shape and characterized by the highest r2/ r1 ratio once encapsulated into iodinated NE were used for animal experimentation. The in vivo investigation showed an excellent contrast modification because of the presence of the selected NEs, for both imaging techniques explored, that is, MRI and X-ray imaging. This work provides the description and in vivo application of a simple and efficient nanoparticulate system capable of enhancing contrast for both preclinical imaging modalities, MRI, and computed tomography.
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Meios de Contraste , Iodo , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita , Tomografia Computadorizada por Raios X/métodos , Animais , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Emulsões , Células HeLa , Humanos , Iodo/química , Iodo/farmacocinética , Iodo/farmacologia , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , CamundongosRESUMO
Composites combining superparamagnetic iron oxide nanoparticles (SPIONs) and polymers are largely present in modern (bio)materials. However, although SPIONs embedded in polymer matrices are classically reported, the mechanical and degradation properties of the polymer scaffold are impacted by the SPIONs. Therefore, the controlled anchoring of SPIONs onto polymer surfaces is still a major challenge. Herein, we propose an efficient strategy for the direct and uniform anchoring of SPIONs on the surface of functionalized-polylactide (PLA) nanofibers via a simple free ligand exchange procedure to design PLA@SPIONs core@shell nanocomposites. The resulting PLA@SPIONs hybrid biomaterials are characterized by electron microscopy (scanning electron microscopy and transmission electron microscopy) and energy-dispersive X-ray spectroscopy analysis to probe the morphology and detect elements present at the organic-inorganic interface, respectively. A monolayer of SPIONs with a complete and homogeneous coverage is observed on the surface of PLA nanofibers. Magnetization experiments show that magnetic properties of the nanoparticles are well preserved after their grafting on the PLA fibers and that the size of the nanoparticles does not change. The absence of cytotoxicity, combined with a high sensitivity of detection in magnetic resonance imaging both in vitro and in vivo, makes these hybrid nanocomposites attractive for the development of magnetic biomaterials for biomedical applications.
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Anticancer agents that target both tumor cells and angiogenesis are of potential interest for glioblastoma (GB) therapy. One such agent is sorafenib (SFN), a tyrosine kinase inhibitor. However, poor aqueous solubility and undesirable side effects limit its clinical application, including local treatment. We encapsulated SFN in lipid nanocapsules (LNCs) to overcome these drawbacks. LNCs are nanocarriers formulated according to a solvent-free process, using only components that have received regulatory approval. SFN-LNCs had a diameter of 54 ± 1 nm, high encapsulation efficiency (>90%), and a drug payload of 2.11 ± 0.03 mg/g of LNC dispersion. They inhibited in vitro angiogenesis and decreased human U87MG GB cell viability similarly to free SFN. In vivo studies showed that the intratumoral administration of SFN-LNCs or free SFN in nude mice bearing an orthotopic U87MG human GB xenograft decreased the proportion of proliferating cells in the tumor relative to control groups. SFN-LNCs were more effective than free SFN for inducing early tumor vascular normalization, characterized by increases in tumor blood flow and decreases in tumor vessel area. These results highlight the potential of LNCs as delivery systems for SFN. The vascular normalization induced by SFN-LNCs could be used to improve the efficacy of chemotherapy or radiotherapy for treating GB.
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Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glioblastoma/tratamento farmacológico , Lipídeos , Nanocápsulas , Sorafenibe/farmacologia , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Composição de Medicamentos/métodos , Humanos , Lipídeos/química , Camundongos , Camundongos Nus , Nanocápsulas/química , Sorafenibe/uso terapêuticoRESUMO
NMR diffusometry is a powerful but challenging method to analyze complex mixture. Each component diffuses differently, from the faster small species to the slower large species, corresponding to different signal attenuation. However, the method is highly sensitive to the quality of the acquired data and the performance of the processing used to resolve multiexponential signals influences. Adapting the signal decay sampling to the mixture composition is one way to improve the precision of the measure. In this work, we propose a prediction tool, based on the calculation of the Cramér-Rao lower bound to minimize the variance of diffusion coefficient estimation in order to determine the optimal number of diffusion gradient steps, the best diffusion gradient sampling (among linear, exponential, quadratic and sigmoidal ones) and the optimal maximum diffusion factor. The tool was validated experimentally on a unimer/micelle solution of sodium dodecyl sulfate and on Caelyx®, a commercial liposomal preparation containing a mixture of pegylated-liposomes and sucrose.
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Soluções/análise , Soluções/química , Difusão , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Lipossomos/química , Micelas , Ressonância Magnética Nuclear Biomolecular/métodos , Polietilenoglicóis/química , Dodecilsulfato de Sódio/químicaRESUMO
AIM: Anticancer drug-loaded hydrogels are a promising strategy for the local treatment of incurable brain tumors such as glioblastoma (GBM). Recently, we demonstrated the efficacy of lauroyl-gemcitabine lipid nanocapsule hydrogel (GemC12-LNC) in a U-87 MG xenograft orthotopic mouse model. In this study, we developed a reliable and reproducible surgical procedure to resect orthotopic GBM tumors in rats. GemC12-LNC hydrogel integrity was tested after brain administration in rats and its anti-tumor efficacy was tested on a 9L syngeneic orthotopic model. RESULTS: We demonstrated that LNC integrity is maintained at least for one week after local administration of GemC12-LNC. GemC12-LNC was able to delay the formation of recurrences in 9L tumor-bearing resected rats, demonstrating the efficacy of this nanomedicine hydrogel in this preclinical model. CONCLUSION: Our results confirm that GemC12-LNC, a hydrogel uniquely formed by a nanocarrier and a cytotoxic drug, could be a promising and safe delivery tool for the local treatment of operable GBM tumors.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Glioblastoma/tratamento farmacológico , Hidrogéis/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/química , Desoxicitidina/uso terapêutico , Feminino , Imageamento por Ressonância Magnética , Nanomedicina/métodos , Ratos , Ratos Sprague-Dawley , GencitabinaRESUMO
Increasing intracellular drug concentration using nanocarriers can be a potential strategy to improve efficacy against glioblastoma (GBM). Here, the fluorescent-labelled NFL-TBS·40-63 peptide (fluoNFL) concentration on a lipid nanocapsule (LNC) was studied to enhance nanovector internalization into human GBM cells. LNC surface-functionalization with various fluoNFL concentrations was performed by adsorption. LNC size and surface charge altered gradually with increasing peptide concentration, but their complement protein consumption remained low. Desorption of fluoNFL from the LNC surface was found to be slow. Furthermore, it was observed that the rate and extent of LNC internalization in the U87MG human glioblastoma cells were dependent on the surface-functionalizing fluoNFL concentration. In addition, we showed that the uptake of fluoNFL-functionalized LNCs was preferential towards U87MG cells compared to healthy human astrocytes. The fluoNFL-functionalized LNC internalization into the U87MG cells was energy-dependent and occurred possibly by macropinocytosis and clathrin-mediated and caveolin-mediated endocytosis. A new ferrocifen-type molecule (FcTriOH), as a potent anticancer candidate, was then encapsulated in the LNCs and the functionalization improved its in vitro efficacy compared to other tested formulations against U87MG cells. In the preliminary study, on subcutaneous human GBM tumor model in nude mice, a significant reduction of relative tumor volume was observed at one week after the second intravenous injection with FcTriOH-loaded LNCs. These results showed that enhancing NFL peptide concentration on the LNC surface is a promising approach for increased and preferential nanocarrier internalization into human GBM cells, and the FcTriOH-loaded LNCs are a promising therapy approach for GBM.