RESUMO
This work takes place in the "cartilage targeting strategy", consisting in using the quaternary ammonium (QA) function as a vector to proteoglycans (PGs) of extracellular matrix (ECM). The objective was to demonstrate that QA could address gadolinium based small rigid platforms (SRP) to PG-rich tumors. SRP were functionalized with QA, radiolabeled with (111)Indium and evaluated for biodistribution in vivo, respectively to non functionalized SRP, in two experimental models: (i) the HEMCSS human xenograft model; (ii) the Swarm rat chondrosarcoma (SRC) orthotopic model. The contribution of cellular uptake to tumoral accumulation of nano-objects was also determined from in vitro binding. In the SRC model expressing a highly and homogeneously distributed PG content, tumor accumulation and retention of SRP@QA were increased by 40% as compared to non-functionalized SRP. When considering the radiosensitizing potential of gadolinium based SRP, these results provide hopes for the radiobiological approach of highly resistant tumor such as chondrosarcoma. FROM THE CLINICAL EDITOR: In this study, gadolinium-based complexing DOTA-surfaced small polysiloxane nanoparticles were functionalized with quaternary ammonium derivatives that target the extracellular matrix of chondrosarcoma. The authors demonstrate in a rat model that the use of these constructs results in a 40% increase of tumor accumulation and retention compared to non-functionalized (and otherwise same) platforms. Similar approaches would be welcome additions to the clinical armamentarium addressing chondrosarcoma.
Assuntos
Compostos de Amônio/química , Condrossarcoma/metabolismo , Nanopartículas/química , Compostos de Amônio/uso terapêutico , Animais , Linhagem Celular Tumoral , Condrossarcoma/tratamento farmacológico , Matriz Extracelular , Gadolínio/química , Humanos , Masculino , Nanopartículas/metabolismo , Ratos , Ratos Sprague-Dawley , Siloxanas/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
To mitigate the risk of radioactive isotope dissemination, the development of preventative and curative measures is of particular interest. For mass treatment, the developed solution must be easily administered, preferably orally, with effective, nontoxic decorporating properties against a wide range of radioactive isotopes. Currently, most orally administered chelation therapy products are quickly absorbed into the blood circulation, where chelation of the radioactive isotope is a race against time due to the short circulation half-life of the therapeutic. This report presents an alternative therapeutic approach by using a functionalized chitosan (chitosan@DOTAGA) with chelating properties that remains within the gastrointestinal tract and is eliminated in feces, that can protect against ingested radioactive isotopes. The polymer shows important in vitro chelation properties towards different metallic cations of importance, including (Cs(I), Ir(III), Th(IV), Tl(I), Sr(II), U(VI) and Co(II)), at different pH (from 1 to 7) representing the different environments in the gastrointestinal tract. An in vivo proof of concept is presented on a rodent model of uranium contamination following an oral administration of Chitosan@DOTAGA. The polymer partially prevents the accumulation of uranium within the kidneys (providing a protective effect) and completely prevents its uptake by the spleen.
Assuntos
Quitosana , Protetores contra Radiação , Urânio , Quitosana/química , Urânio/química , Protetores contra Radiação/farmacologia , Polímeros , Quelantes/químicaRESUMO
New, ultrasmall nanoparticles with sizes below 5â nm have been obtained. These small rigid platforms (SRP) are composed of a polysiloxane matrix with DOTAGA (1,4,7,10-tetraazacyclododecane-1-glutaric anhydride-4,7,10-triacetic acid)-Gd(3+) chelates on their surface. They have been synthesised by an original top-down process: 1)â formation of a gadolinium oxide Gd2O3 core, 2)â encapsulation in a polysiloxane shell grafted with DOTAGA ligands, 3)â dissolution of the gadolinium oxide core due to chelation of Gd(3+) by DOTAGA ligands and 4)â polysiloxane fragmentation. These nanoparticles have been fully characterised using photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), a superconducting quantum interference device (SQUID) and electron paramagnetic resonance (EPR) to demonstrate the dissolution of the oxide core and by inductively coupled plasma mass spectrometry (ICP-MS), mass spectrometry, fluorescence spectroscopy, (29)Si solid-state NMR, (1)Hâ NMR and diffusion ordered spectroscopy (DOSY) to determine the nanoparticle composition. Relaxivity measurements gave a longitudinal relaxivity r1 of 11.9â s(-1) mM(-1) per Gd at 60â MHz. Finally, potentiometric titrations showed that Gd(3+) is strongly chelated to DOTAGA (complexation constant logß110 =24.78) and cellular tests confirmed the that nanoconstructs had a very low toxicity. Moreover, SRPs are excreted from the body by renal clearance. Their efficiency as contrast agents for MRI has been proved and they are promising candidates as sensitising agents for image-guided radiotherapy.
Assuntos
Gadolínio/química , Compostos Heterocíclicos com 1 Anel/química , Dióxido de Silício/química , Siloxanas/química , Substância P/análogos & derivados , Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Radioterapia Guiada por Imagem , Espectrometria de Fluorescência , Substância P/químicaRESUMO
This paper presents energy transfer occurring in small organically modified core-shell nanoparticles (core lanthanide oxide, shell polysiloxane) (diameter < 10 nm) conjugated with photosensitizers designed for photodynamic therapy applications. These nanoparticles covalently encapsulate a photosensitizing PDT drug in different concentrations. Stable dispersions of the nanoparticles were prepared and the photophysical properties of the photosensitizers were studied and compared to those of the photosensitizers in solution. Increasing the photosensitizer concentration in the nanoparticles was not found to cause any changes in the absorption properties while fluorescence and singlet oxygen quantum yields decreased. As a possible explanation, we have suggested that both long distance energy transfer such as FRET and self-quenching could occur into the nanoparticles. A simple "trend" model of this kind of energy transfer complies with results of experiments on steady state fluorescence and singlet oxygen luminescence.
Assuntos
Nanopartículas/química , Fármacos Fotossensibilizantes/química , Portadores de Fármacos/química , Transferência de Energia , Fluorescência , Transferência Ressonante de Energia de Fluorescência , Humanos , Lantânio/química , Luminescência , Modelos Químicos , Neoplasias/tratamento farmacológico , Óxidos/química , Processos Fotoquímicos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Siloxanas/química , Oxigênio Singlete/química , Espectrometria de FluorescênciaRESUMO
Interest of tumor targeting through EPR effect is still controversial due to intrinsic low targeting efficacy and rare translation to human cancers. Moreover, due to different reasons, it has generally been described for relatively large nanoparticles (NPs) (hydrodynamic diameter > 10 nm). In this review EPR effect will be discussed for ultrasmall NPs using the example of the AGuIX® NP (Activation and Guiding of Irradiation by X-ray) recently translated in clinic. AGuIX® NP is a 4 ± 2 nm hydrodynamic diameter polysiloxane based NP. Since AGuIX® NP biodistribution is monitored by magnetic resonance imaging (MRI) and its activation is triggered by irradiation upon X-rays, this NP is well adapted for a theranostic approach of radiotherapy cancer treatment. Here we show that AGuIX® NP is particularly well suited to benefit from EPR-mediated tumor targeting thanks to an ultrasmall size and efficacy under irradiation at small dose. Indeed, intravenously-injected AGuIX® NP into rodent cancer models passively reached the tumor and revealed no toxicity, favoured by renal clearance. Moreover, translation of AGuIX® NP accumulation and retention into humans carrying brain metastases was validated during a first-in-man phase Ib trial taking advantage of easy biodistribution monitoring by MRI.
Assuntos
Gadolínio , Nanopartículas/química , Neoplasias , Nanomedicina Teranóstica , Animais , Quelantes/química , Gadolínio/farmacocinética , Gadolínio/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Tamanho da Partícula , Siloxanas/química , Distribuição TecidualRESUMO
Glioblastoma is the most aggressive primary brain tumor leading to death in most of patients. It comprises almost 50-55% of all gliomas with an incidence rate of 2-3 per 100,000. Despite its rarity, overall mortality of glioblastoma is comparable to the most frequent tumors. The current standard treatment combines surgical resection, radiotherapy and chemotherapy with temozolomide. In spite of this aggressive multimodality protocol, prognosis of glioblastoma is poor and the median survival remains about 12-14.5 months. In this regard, new therapeutic approaches should be developed to improve the life quality and survival time of the patient after the initial diagnosis. Before switching to clinical trials in humans, all innovative therapeutic methods must be studied first on a relevant animal model in preclinical settings. In this regard, we validated the feasibility of intratumoral delivery of a holmium (Ho) microparticle suspension to an induced U87 glioblastoma model. Among the different radioactive beta emitters, 166Ho emits high-energy ß(-) radiation and low-energy γ radiation. ß(-) radiation is an effective means for tumor destruction and γ rays are well suited for imaging (SPECT) and consequent dosimetry. In addition, the paramagnetic Ho nucleus is a good asset to perform MRI imaging. In this study, five minipigs, implanted with our glioblastoma model were used to test the injectability of 165Ho (stable) using a bespoke injector and needle. The suspension was produced in the form of Ho microparticles and injected inside the tumor by a technique known as microbrachytherapy using a stereotactic system. At the end of this trial, it was found that the 165Ho suspension can be injected successfully inside the tumor with absence or minimal traces of Ho reflux after the injections. This injection technique and the use of the 165Ho suspension needs to be further assessed with radioactive 166Ho in future studies.
Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Hólmio/química , Compostos Radiofarmacêuticos/administração & dosagem , Siloxanas/química , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Humanos , Masculino , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Suínos , Porco Miniatura , Tomografia Computadorizada de Emissão de Fóton Único , Transplante HeterólogoRESUMO
Fluorescent nanoparticles containing a gadolinium oxide core are very attractive because they are able to combine both imaging (fluorescence imaging, magnetic resonance imaging) and therapy (X-ray therapy and neutron-capture therapy) techniques. The exploitation of these multifunctional particles for in vivo applications requires accurate control of their biodistribution. The postfunctionalization of these particles by four different poly(ethylene glycol) derivatives, which differ by chain length and end group, exerts a great influence on the zeta potential of the nanoparticles and on their biodistribution after intravenous injection to HEK-beta3-tumor-bearing mice. This study reveals that the behavior of PEGylated nanoparticles, which was monitored by in vivo fluorescence imaging, depends on both the chain length and the end group of the PEG chain.
Assuntos
Gadolínio/farmacocinética , Neoplasias Renais/metabolismo , Nanopartículas/química , Polietilenoglicóis/farmacocinética , Animais , Linhagem Celular Tumoral , Materiais Revestidos Biocompatíveis/farmacocinética , Neoplasias Renais/diagnóstico , Espectroscopia de Ressonância Magnética/métodos , Taxa de Depuração Metabólica , Camundongos , Camundongos Nus , Nanopartículas/ultraestrutura , Especificidade de Órgãos , Distribuição TecidualRESUMO
Au and Ag biochips were fabricated to investigate the influence of pH upon the chemiluminescence (CL) of luminol at vicinity of surface-adsorbed peroxidase. A nanoscaled-corrugation of the metal induces an enhancement of the luminol CL which is maximal in the pH range favoring peroxidase catalysis and greater for gold than for silver. This is the proof that, in the CL process, the reactions involving peroxidase are surface-enhanced near corrugated surfaces.
Assuntos
Ouro/química , Luminol/química , Luminol/metabolismo , Membranas Artificiais , Nanopartículas Metálicas/química , Peroxidase/metabolismo , Prata/química , Adsorção , Biocatálise , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio , Luminescência , Nanotecnologia , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
AIM: The aim of this study was to develop a dual-modality positron emission tomography/magnetic resonance (PET/MR) imaging probe by radiolabeling gadolinium-containing AGuIX derivatives with the positron-emitter Gallium-68 (68Ga). MATERIALS & METHODS: AGuIX@NODAGA nanoparticles were labeled with 68Ga at high efficiency. Tumor accumulation in an appropriate disease model was assessed by ex vivo biodistribution and in vivo PET/MR imaging. RESULTS: 68Ga-AGuIX@NODAGA was proven to passively accumulate in U87MG human glioblastoma tumor xenografts. Metabolite assessment in serum, urine and tumor samples showed that 68Ga-AGuIX@NODAGA remains unmetabolized up to at least 60 min postinjection. CONCLUSION: This study demonstrates that 68Ga-AGuIX@NODAGA can be used as a dual-modality PET/MR imaging agent with passive accumulation in the diseased area, thus showing great potential for PET/MR image-guided radiation therapy.
Assuntos
Acetatos/química , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Meios de Contraste/química , Complexos de Coordenação/química , Radioisótopos de Gálio/química , Glioblastoma/diagnóstico por imagem , Compostos Heterocíclicos com 1 Anel/química , Nanopartículas/química , Siloxanas/química , Animais , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/radioterapia , Cromatografia Líquida de Alta Pressão , Feminino , Radioisótopos de Gálio/sangue , Radioisótopos de Gálio/urina , Glioblastoma/radioterapia , Humanos , Imageamento por Ressonância Magnética/métodos , Camundongos , Camundongos SCID , Tomografia por Emissão de Pósitrons/métodos , Distribuição TecidualRESUMO
We previously reported the synthesis of gadolinium-based nanoparticles (NPs) denoted AGuIX (activation and guiding of irradiation by X-ray) NPs and demonstrated their potential as an MRI contrast agent and their efficacy as radiosensitizing particles during X-ray cancer treatment. Here we focus on the elimination kinetics of AGuIX NPs from the subcellular to whole-organ scale using original and complementary methods such as laser-induced breakdown spectroscopy (LIBS), intravital two-photon microscopy, inductively coupled plasma optical emission spectrometry (ICP-OES), transmission electron microscopy (TEM), and electrospray ionization mass spectrometry (ESI-MS). This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated, including their retention in proximal tubules and their excretion as degraded or native NPs. Finally, we demonstrated that systemic AGuIX NP administration induced moderate and transient effects on renal function. These results provide useful and promising preclinical information concerning the safety of theranostic AGuIX NPs.
Assuntos
Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Meios de Contraste/química , Meios de Contraste/farmacocinética , Gadolínio/química , Gadolínio/farmacocinética , Nanopartículas Metálicas , Animais , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/toxicidade , Transporte Biológico , Meios de Contraste/metabolismo , Meios de Contraste/toxicidade , Gadolínio/metabolismo , Gadolínio/toxicidade , Humanos , Injeções , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Cinética , Camundongos , Modelos Moleculares , Conformação Molecular , Segurança , Raios XRESUMO
The synthesis, optical properties and efficiency of new multifunctional nanoparticles as theranostic (fluorescence/MRI/PDT) agents are described. They are based on a polysiloxane network and surrounded by gadolinium(III) chelates and ruthenium(II) complexes. The size of the nanoparticles is maintained under 5 nm in order to permit their efficient elimination from the body. Their potential use as a theranostic agent (PDT/MRI) is described. The magnetic properties of the nanoparticles are studied by relaxometry (r1 = 9.21 mM(-1) s(-1) at 40 MHz; r2/r1 = 1.14) and the signal enhancement is validated by the acquisition of phantoms on a 3 T MRI imager. The therapeutic potential for photodynamic therapy of the nanoparticles has been studied in vitro on HEK293 cells and an effective quantum yield of 0.33 for (1)O2 production has been determined in deuterated water.
Assuntos
Complexos de Coordenação/química , Gadolínio/química , Nanopartículas Metálicas/química , Fármacos Fotossensibilizantes/química , Rutênio/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Células HEK293 , Humanos , Luz , Imageamento por Ressonância Magnética , Nanopartículas Metálicas/toxicidade , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/toxicidade , Siloxanas/química , Oxigênio Singlete/químicaRESUMO
Nanostructured Tb(3+)-doped Gd(2)O(3) particles have been synthesized from chloride precursors by NaOH addition in a polyol medium. In-situ luminescent spectra have been investigated in order to follow up the process of formation and growth of these particles by varying parameters as the elaboration temperature and the rate of NaOH addition. Contrarily to all the literature related to the "polyol" synthesis, the paper proves that oxide particles can be directly formed at room temperature. These particles are also slightly bigger and organized in nanorods when NaOH is added progressively. Finally, it was found that the influence of further annealing up to 160 degrees C strongly depends on the NaOH addition rate. While preserving the oxide phase, annealing leads to bigger particles only in the case of a progressive addition of NaOH.
Assuntos
Gadolínio/química , Luminescência , Nanopartículas/química , Nanotecnologia/métodos , Térbio/química , Cloretos/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Polímeros/química , Hidróxido de Sódio/química , TemperaturaRESUMO
For labeling proteins (streptavidin and fibronectin) by luminescent aminated nanoparticles, an interesting strategy that requires neither activation nor chemical pre- or post-treatment was explored. Because biomolecules are easily rendered luminescent after reaction with organic dyes carrying isothiocyanate moiety, phenylene diisothiocyanate (DITC) was used for covalently binding proteins onto luminescent hybrid gadolinium oxide nanoparticles whose ability to combine imaging and therapy was recently demonstrated.
Assuntos
Medições Luminescentes/instrumentação , Nanopartículas/química , Nanotecnologia/métodos , Biotina/química , Corantes/química , Cristalização , Fibronectinas/química , Gadolínio/química , Medições Luminescentes/métodos , Teste de Materiais , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Fotoquímica/instrumentação , Fotoquímica/métodos , Prótons , Siloxanas/química , Estreptavidina/químicaRESUMO
Luminescent hybrid nanoparticles with a paramagnetic Gd2O3 core were applied as contrast agents for both in vivo fluorescence and magnetic resonance imaging. These hybrid particles were obtained by encapsulating Gd2O3 cores within a polysiloxane shell which carries organic fluorophores and carboxylated PEG covalently tethered to the inorganic network. Longitudinal proton relaxivities of these particles are higher than the positive contrast agents like Gd-DOTA which are commonly used for clinical magnetic resonance imaging. Moreover these particles can be followed up by fluorescence imaging. This study revealed that these particles suited for dual modality imaging freely circulate in the blood vessels without undesirable accumulation in lungs and liver.