RESUMO
In this work we adapt rare-earth-ion-doped NaYF4nanoparticles coated with a silicon oxide shell (NaYF4:20%Yb,0.2%Tm@SiO2) for biological and medical applications (for example, imaging of cancer cells and therapy at the nano level). The wide upconversion emission range under 980 nm excitation allows one to use the nanoparticles for cancer cell (4T1) photodynamic therapy (PDT) without a photosensitizer. The reactive oxygen species (ROS) are generated by Tm/Yb ion upconversion emission (blue and UV light). Thein vitroPDT was tested on 4T1 cells incubated with NaYF4:20%Yb,0.2%Tm@SiO2nanoparticles and irradiated with NIR light. After 24 h, cell viability decreased to below 10%, demonstrating very good treatment efficiency. High modification susceptibility of the SiO2shell allows for attachment of biological molecules (specific antibodies). In this work we attached the anti-human IgG antibody to silane-PEG-NHS-modified NaYF4:20%Yb,0.2%Tm@SiO2nanoparticles and a specifically marked membrane model by bio-conjugation. Thus, it was possible to perform a selective search (a high-quality optical method with a very low-level organic background) and eventually damage the targeted cancer cells. The study focuses on therapeutic properties of NaYF4:20%Yb,0.2%Tm@SiO2nanoparticles and demonstrates, upon biological functionalization, their potential for targeted therapy.
Assuntos
Nanopartículas , Neoplasias , Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia , Túlio/química , Túlio/farmacocinética , Túlio/farmacologia , Itérbio/química , Itérbio/farmacocinética , Itérbio/farmacologia , Ítrio/química , Ítrio/farmacocinética , Ítrio/farmacologiaRESUMO
Radiopharmaceuticals with therapeutic applications are designed to deliver high doses of radiation to target organs with minimizing unwanted radiation to healthy tissues. Owing to the potential of targeted radiotherapy to treat a wide range of malignancies, 170Tm -EDTMP was developed for possible therapeutic applications. This study describes absorbed dose prediction of 170Tm-EDTMP in human organs after animal injection which is determined via medical internal radiation dose (MIRD) and MCNP-4C code methods. It was estimated that a 1-MBq administration of 170Tm-EDTMP into the human body would result in an absorbed dose of 37.9 mGy (MIRD method) and 38.02 mGy (MCNP-4C code) in the bone surface after 60 days post injection. Highest and lowest difference between MIRD and MCNP results are for lung and bone surface respectively. Finally, the results show that there is a good agreement between MIRD method and MCNP-4C simulation code for absorbed dose estimation.
Assuntos
Neoplasias Ósseas/radioterapia , Compostos Organometálicos/uso terapêutico , Organofosfonatos/uso terapêutico , Dor/radioterapia , Radiometria/métodos , Animais , Neoplasias Ósseas/fisiopatologia , Neoplasias Ósseas/secundário , Simulação por Computador , Humanos , Camundongos , Modelos Animais , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Manejo da Dor/métodos , Cuidados Paliativos/métodos , Radioisótopos/administração & dosagem , Radioisótopos/farmacocinética , Radioisótopos/uso terapêutico , Radiometria/estatística & dados numéricos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Ratos , Túlio/administração & dosagem , Túlio/farmacocinética , Túlio/uso terapêutico , Distribuição TecidualRESUMO
Rare-earth upconversion nanoparticles (UCNPs) are considered stable nanoprobes with low toxicity and deep tissue penetration. However, the increasing use of UCNPs has raised concerns about their potential toxicity in living organisms. Very few studies have reported the toxicity of UCNPs; hence, it is not possible to conclude yet that UCNPs are safe. In this study, the distribution of PEGylated NaYF4:Yb/Tm/Gd nanoparticles (PEG-UCNPs) in female Balb/c mice following intravenous administration, and imaging in the spleen, liver and kidney was examined by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). PEG-UCNPs distributed primarily to the liver and spleen, with significant but lower levels being noted in the kidneys, heart, and lungs. At the sub-organ level, PEG-UCNPs mainly accumulated within the red pulp of the spleen instead of the white pulp, which indicated that PEG-UCNPs are poorly immunogenic, or not immunogenic at all. The imaging of Cu in the liver and spleen showed that the primary clearance organ for PEG-UCNPs is the liver, although they are accumulated in the spleen rather than the liver. This can be explained by the fact that excess superoxide anions produced by phagocytosis of the PEG-UCNPs need Cu-Zn-superoxide dismutase to be converted to hydrogen peroxide. From the Fe, Cu, and Zn imaging of the kidney, it was concluded that PEG-UCNPs do not exhibit nephrotoxicity.
Assuntos
Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Imagem Molecular/métodos , Nanopartículas/toxicidade , Polietilenoglicóis/química , Baço/efeitos dos fármacos , Animais , Feminino , Fluoretos/química , Fluoretos/farmacocinética , Gadolínio/química , Gadolínio/farmacocinética , Rim/metabolismo , Terapia a Laser , Fígado/metabolismo , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Baço/metabolismo , Túlio/química , Túlio/farmacocinética , Distribuição Tecidual , Itérbio/química , Itérbio/farmacocinética , Ítrio/química , Ítrio/farmacocinéticaRESUMO
The objective of the present work is to formulate 170Tm-EDTMP using an in-house freeze-dried EDTMP kit and evaluate its potential as a bone pain palliation agent. Patient dose of 170Tm-EDTMP was prepared with high radiochemical purity using the lyophilized kit at room temperature within 15min. Pre-clinical evaluation in normal Wistar rats revealed selective skeletal accumulation with extended retention. Preliminary clinical investigation in 8 patients with disseminated skeletal metastases exhibited selective uptake in the bone and retention therein for a long duration.
Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Osso e Ossos/metabolismo , Liofilização , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Dor Intratável/tratamento farmacológico , Cuidados Paliativos/métodos , Idoso , Animais , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Animais , Dor Intratável/metabolismo , Ratos Wistar , Túlio/administração & dosagem , Túlio/farmacocinética , Distribuição TecidualRESUMO
The combination therapy has exhibited important potential for the treatment of cancers, especially for drug-resistant cancers. In this report, bi-functional nanoprobes based on doxorubicin (DOX)-loaded NaYF4:Yb/Tm-TiO2 inorganic photosensitizers (FA-NPs-DOX) were synthesized for in vivo near infrared (NIR)-triggered inorganic photodynamic therapy (PDT) and enhanced chemotherapy to overcome the multidrug resistance (MDR) in breast cancers. Using the up-conversion luminescence (UCL) performance of NaYF4:Yb/Tm converting near-infrared (NIR) into ultraviolent (UV) lights, reactive oxygen species (ROS) were triggered from TiO2 inorganic photosensitizers for PDT under the irradiation of a 980 nm laser, by which the deep-penetration and low photo-damage could be reached. Moreover, nanocarrier delivery and folic acid (FA) targeting promoted the cellular uptake, and accelerated the release of DOX in drug-sensitive MCF-7 and resistant MCF-7/ADR cells. The toxicity assessment in vitro and in vivo revealed the good biocompatibility of the as-prepared FA-NPs-DOX nanocomposites. By the combination of enhanced chemotherapy and NIR-triggered inorganic PDT, the viability of MCF-7/ADR cells could decrease by 53.5%, and the inhibition rate of MCF-7/ADR tumors could increase up to 90.33%, compared with free DOX. Therefore, the MDR of breast cancers could be obviously overcome by enhanced chemotherapy and NIR-triggered inorganic PDT of FA-NPs-DOX nanocomposites under the excitation of a 980 nm laser.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Mama/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Fluoretos/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Titânio/uso terapêutico , Ítrio/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Mama/patologia , Neoplasias da Mama/patologia , Doxorrubicina/farmacocinética , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoretos/farmacocinética , Humanos , Raios Infravermelhos , Células MCF-7 , Camundongos Nus , Nanocompostos/uso terapêutico , Nanocompostos/ultraestrutura , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Túlio/farmacocinética , Túlio/uso terapêutico , Itérbio/farmacocinética , Itérbio/uso terapêutico , Ítrio/farmacocinéticaRESUMO
Due to the fact that cellular therapies are increasingly finding application in clinical trials and promise success by treatment of fatal diseases, monitoring strategies to investigate the delivery of the therapeutic cells to the target organs are getting more and more into the focus of modern in vivo imaging methods. In order to monitor the distribution of the respective cells, they can be labeled with lanthanide complexes such as thulium-1,4,7,10-tetraazacyclodoecane-α,α,α,α-tetramethyl-1,4,7,10-tetraacetic acid (Tm(DOTMA)). In this study, experiments on a mouse model with two different cell types, namely, tumor cells and macrophages labeled with Tm(DOTMA), were performed. The systemic distribution of Tm(DOTMA) of both cell types was investigated by means of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICPMS). Using the high resolution of 25 µm, distribution maps of Tm in different tissues such as tumor, liver, lung, and spleen as well as in explanted gel pellets were generated and the behavior of the labeled cells inside the tissue was investigated. Additionally, quantitative data were obtained using homemade matrix-matched standards based on egg yolk. Using this approach, limits of detection and quantification of 2.2 and 7.4 ng·g(-1), respectively, and an excellent linearity over the concentration range from 0.01 to 46 µg·g(-1) was achieved. The highest concentration of the label agent, 32.4 µg·g(-1), in tumor tissue was observed in the area of the injection of the labeled tumor cells. Regarding the second experiment with macrophages for cell tracking, Tm was detected in the explanted biogell pellet with relatively low concentrations below 60 ng·g(-1) and in the liver with a relatively high concentration of 10 µg·g(-1). Besides thulium, aluminum was detected with equal distribution behavior in the tumor section due to a contamination resulting from the labeling procedure, which includes the usage of an Al electrode.
Assuntos
Rastreamento de Células , Lasers , Compostos Organometálicos/análise , Compostos de Amônio Quaternário/análise , Túlio/análise , Animais , Imageamento por Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Nus , Compostos Organometálicos/farmacocinética , Prótons , Compostos de Amônio Quaternário/farmacocinética , Túlio/farmacocinética , Distribuição TecidualRESUMO
OBJECTIVE: Thulium-170 [T1/2=128.4 days, Eß(max)=968 keV, and Eγ=84 keV (3.26%)] could be considered an easily producible and cost-effective alternative to (89)Sr for the preparation of radiopharmaceuticals for palliation of bone pain arising due to skeletal metastases. Multidentate aminomethylene polyphosphonic acids have already been proven to be effective as carrier moieties for developing radiolabeled bone pain palliation agents using lanthanide radionuclides. Therefore, an attempt was made to evaluate the potential of a series of (170)Tm-labeled acyclic (diethylenetriaminepentamethylene phosphonic acid and triethylenetetraminehexamethylene phosphonic acid) and cyclic polyaminopolyphosphonic acids (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid [DOTMP] and 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetramethylene phosphonic acid [CTMP]) toward their use as alternative bone pain palliation agents. EXPERIMENTAL: Thulium-170 was produced by irradiating the natural Tm2O3 target at a thermal neutron flux of 7×10(13) n·cm(-2)·s(-1) for a period of 60 days. All the phosphonic acid ligands were synthesized and characterized in-house. The protocols for radiolabeling the phosphonic acids with (170)Tm were standardized. Biological evaluation of the (170)Tm-labeled phosphonic acids were carried out in normal Wistar rats by biodistribution as well as by scintigraphic studies. RESULTS: Thulium-170 was produced with adequate specific activity (173 Ci/g, 6.41 TBq/g) and high radionuclidic purity (99.62%). All the (170)Tm-labeled phosphonic acids, except (170)Tm-CTMP, were prepared with very high radiochemical purity (>98%) under optimized reaction conditions and exhibited high stability. All the agents showed selective skeletal accumulation with insignificant uptake in other vital organs/tissues and major clearance through renal pathway. These findings were also substantiated by scintigraphic studies. CONCLUSIONS: Although all the (170)Tm-labeled phosphonic acids showed significant and selective skeletal accumulation, radiochemical studies indicate that (170)Tm-DOTMP is the best choice for carrying out further evaluation toward its use for clinical applications.
Assuntos
Osso e Ossos/diagnóstico por imagem , Ácidos Fosforosos/farmacocinética , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Túlio/química , Túlio/farmacocinética , Animais , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Marcação por Isótopo , Cuidados Paliativos , Ácidos Fosforosos/química , Poliaminas/química , Poliaminas/farmacocinética , Radioisótopos/química , Cintilografia , Compostos Radiofarmacêuticos/química , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
Upconversion luminescence (UCL) properties and radioactivity have been integrated into NaLuF(4):(153)Sm,Yb,Tm nanoparticles by a facile one-step hydrothermal method, making these nanoparticles potential candidates for UCL and single-photon emission computed tomography (SPECT) dual-modal bioimaging in vivo. The introduction of small amount of radioactive (153)Sm(3+) can hardly vary the upconversion luminescence properties of the nanoparticles. The as-designed nanoparticles showed very low cytotoxicity, no obvious tissue damage in 7 days, and excellent in vitro and in vivo performances in dual-modal bioimaging. By means of a combination of UCL and SPECT imaging in vivo, the distribution of the nanoparticles in living animals has been studied, and the results indicated that these particles were mainly accumulated in the liver and spleen. Therefore, the concept of (153)Sm(3+)/Yb(3+)/Tm(3+) co-doped NaLuF(4) nanoparticles for UCL and SPECT dual-modality imaging in vivo of whole-body animals may serve as a platform for next-generation probes for ultra-sensitive molecular imaging from the cellular scale to whole-body evaluation. It also introduces an easy methodology to quantify in vivo biodistribution of nanomaterials which still needs further understanding as a community.
Assuntos
Compostos de Flúor/química , Nanopartículas/análise , Imagem Óptica/métodos , Samário/química , Túlio/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Itérbio/química , Animais , Linhagem Celular Tumoral , Compostos de Flúor/farmacocinética , Compostos de Flúor/toxicidade , Humanos , Luminescência , Medições Luminescentes/métodos , Lutécio/química , Lutécio/farmacocinética , Lutécio/toxicidade , Camundongos , Nanopartículas/toxicidade , Nanopartículas/ultraestrutura , Radioisótopos/química , Radioisótopos/farmacocinética , Radioisótopos/toxicidade , Samário/farmacocinética , Samário/toxicidade , Sódio/química , Sódio/farmacocinética , Sódio/toxicidade , Túlio/farmacocinética , Túlio/toxicidade , Distribuição Tecidual , Itérbio/farmacocinética , Itérbio/toxicidadeRESUMO
Paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents are under development for biological target identification by magnetic resonance imaging. Image contrast associated with PARACEST agents can be generated by radiofrequency irradiation of the chemically shifted protons bound to a PARACEST contrast agent molecule or by direct irradiation of the on-resonance bulk water protons. The observed signal change in a magnetic resonance image after the administration of a PARACEST contrast agent is due to both altered relaxation time constants and the CEST effect. Despite high sensitivity in vitro, PARACEST agents have had limited success in vivo where sensitivity is reduced by the magnetization transfer effect from endogenous macromolecules. The purpose of this study was to demonstrate the in vivo detection of a PARACEST contrast agent using the on-resonance paramagnetic chemical exchange effect (OPARACHEE) in a mouse glioblastoma multiforme tumor model and to isolate the OPARACHEE effect from the changes in relaxation induced by the PARACEST agent. Three mice with tumors were imaged on a 9.4 T MRI scanner following tail vein injection of 150 µL 50 mM Tm(3+)-DOTAM-glycine-lysine. A fast low angle shot pulse sequence with a low power radiofrequency pulse train (WALTZ-16) as the preparation pulse was used to generate OPARACHEE contrast. To study the dynamics of agent uptake, reference images (without the preparation pulse) and OPARACHEE images were acquired continuously in an alternating fashion before, during and after agent injection. Signal intensity decreased by more than 10% in tumor in the control images after agent administration. Despite these changes, a clear OPARACHEE contrast of 1-5% was also observed in brain tumors after contrast agent injection and maintained in the hour following injection. This result is the first in vivo observation of OPARACHEE contrast in brain tumors with correction of T(1) and T(2) relaxation effects.