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1.
Chemphyschem ; 21(3): 251-256, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31922367

RESUMO

The promise of hyperpolarized glucose as a non-radioactive imaging agent capable of reporting on multiple metabolic routes has led to recent advances in its dissolution-DNP (dDNP) driven polarization using UV-light induced radicals and trityl radicals at high field (6.7 T) and 1.1 K. However, most preclinical dDNP polarizers operate at the field of 3.35 T and 1.4-1.5 K. Minute amounts of Gd3+ complexes have shown large improvements in solid-state polarization, which can be translated to improved hyperpolarization in solution. However, this Gd3+ effect seems to depend on magnetic field strength, metal ion concentration, and sample formulation. The effect of varying Gd3+ concentrations at 3.35 T has been described for 13 C-labeled pyruvic acid and acetate. However, it has not been studied for other compounds at this field. The results presented here suggest that Gd3+ doping can lead to various concentration and temperature dependent effects on the polarization of [13 C6 ,2 H7 ]glucose, not necessarily similar to the effects observed in pyruvic acid or acetate in size or direction. The maximal polarization for [13 C6 ,2 H7 ]glucose appears to be at a Gd3+ concentration of 2 mM, when irradiating for more than 2 h at the negative maximum of the DNP intensity profile. Surprisingly, for shorter irradiation times, higher polarization levels were determined at 1.50 K compared to 1.45 K, at a [Gd3+ ]=1.3 mM. This was explained by the build-up time constant and maximum at these temperatures.


Assuntos
Gadolínio/química , Glucose/química , Isótopos de Carbono , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Deutério , Ácido Pirúvico/química
2.
J Phys Chem Lett ; 11(3): 1141-1147, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31951412

RESUMO

Double-electron electron resonance (DEER) can be used to track the structural dynamics of proteins in their native environment, the cell. This method provides the distance distribution between two spin labels attached at specific, well-defined positions in a protein. For the method to be viable under in-cell conditions, the spin label and its attachment to the protein should exhibit high chemical stability in the cell. Here we present low-temperature, trityl-trityl DEER distance measurements on two model proteins, PpiB (prolyl cis-trans isomerase from E. coli) and GB1 (immunoglobulin G-binding protein), doubly labeled with the trityl spin label, CT02MA. Both proteins gave in-cell distance distributions similar to those observed in vitro, with maxima at 4.5-5 nm, and the data were further compared with in-cell Gd(III)-Gd(III) DEER obtained for PpiB labeled with BrPSPy-DO3A-Gd(III) at the same positions. These results highlight the challenges of designing trityl tags suitable for in-cell distance determination at ambient temperatures on live cells.


Assuntos
Proteínas de Bactérias/química , Proteínas de Transporte/química , Ciclofilinas/química , Espectroscopia de Ressonância de Spin Eletrônica , Compostos de Tritil/química , Gadolínio/química , Marcadores de Spin
3.
J Photochem Photobiol B ; 202: 111669, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31739258

RESUMO

Herein we report the synthesis and characterization of the antifouling Gadolinium oxide (Gd2O3) nanoparticles (NPs) modified with PEG with improved biocompatibility for MR imaging purposes. In this report, using the solvothermal decomposition of Gadolinium (III) in the presence of Na3cit, monitored by surface modification with PEG and L-Cys. The synthesized nanoparticles were confirmed by the TEM, DLS and UV-Visible spectroscopy. The morphological results show normal distance across of the flawless Gd2O3-PEG-Cys-NPs show 7.9 ±â€¯0.4 nm, discretely, with a thin size exchange. This infers the surface adjustment does not obviously alteration the center size of the Gd2O3-NPs when contrasted with the perfect sodium citrate-balanced out Gd2O3-NPs. The Gd2O3-PEG-L-Cys-NPs are highly stable at room temperature, water dispersible and importantly less cytotoxic at high concentration of the NPs. The T1-weighted MR phantasm readings evidentially displayed that the formed PEG coated Gd2O3-PEG and Gd2O3-PEG-Cys-NPs with and without Cys may be performed as the promising T1-weighted MR imaging. The NPs displays no signs of toxicity against the human blood, which represents the biocompatibility for the human medicine applications. The Gd2O3-PEG-Cys-NPs shows relatively, high r1 acceptable cytocompatibility, target specific cancer cells and activate the dual mode MR imaging of lung metastasis cancer model in vitro. The development of versatile zwitterion functionalized Gd2O3 may be promising as an active nanoparticle probe for improved multi-model of MR imaging agents for various cancer diseases.


Assuntos
Meios de Contraste/química , Gadolínio/química , Neoplasias Pulmonares/diagnóstico por imagem , Imagem por Ressonância Magnética , Nanopartículas/química , Polietilenoglicóis/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisteína/química , Hemólise/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/secundário , Melanoma Experimental/patologia , Camundongos , Nanopartículas/toxicidade , Células RAW 264.7 , Transplante Homólogo
4.
Int J Nanomedicine ; 14: 9309-9324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819433

RESUMO

Introduction: The development of biopolymers for the synthesis of Gd(III) nanoparticles, as therapeutics, could play a key role in nanomedicine. Biocompatible polymers are not only used for complex monovalent biomolecules, but also for the realization of multivalent active targeting materials as diagnostic and/or therapeutic hybrid nanoparticles. In this article, it was reported for the first time, a novel synthesis of Gd(III)-biopolymer-Au(III) complex, acting as a key ingredient of core-shell gold nanoparticles (Gd(@AuNPs). Material and methods: The physical and chemical evaluation was carried out by spectroscopic analytical techniques (Raman spectroscopy, UV-visible and TEM). The theoretical characterization by DFT (density functional theory) analysis was carried out under specific conditions to investigate the interaction between the Au and the Gd precursors, during the first nucleation step. Magnetic features with relaxivity measurements at 7T were also performed as well as cytotoxicity studies on hepatocyte cell lines for biocompatibility studies. The in vivo detailed dynamic biodistribution studies in mice to characterize the potential applications for biology as MRI contrast agents were then achieved. Results: Physical-chemical evaluation confirms the successful design and reaction supposed. Viabilities of TIB-75 (hepatocytes) cells were evaluated using Alamar blue cytotoxic tests with increasing concentrations of nanoparticles. In vivo biodistribution studies were then accomplished to assess the kinetic behavior of the nanoparticles in mice and characterize their stealthiness property after intravenous injection. Conclusion: We demonstrated that Gd@AuNPs have some advantages to display hepatocytes in the liver. Particularly, these nanoconjugates give a good cellular uptake of several quantities of Gd@NPs into cells, while preserving a T1 contrast inside cells that provide a robust in vivo detection using T1-weighted MR images. These results will strengthen the role of gadolinium as complex to gold in order to tune Gd(@AuNPs) as an innovative diagnostic agent in the field of nanomedicine.


Assuntos
Meios de Contraste/química , Gadolínio/química , Ouro/química , Nanopartículas Metálicas/química , Nanomedicina/métodos , Animais , Morte Celular , Sobrevivência Celular , Liberação Controlada de Fármacos , Cinética , Imagem por Ressonância Magnética , Nanopartículas Metálicas/ultraestrutura , Camundongos Endogâmicos BALB C , Polímeros/química , Distribuição Tecidual
5.
Chem Commun (Camb) ; 55(98): 14844-14847, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31768507

RESUMO

Ultrasmall sub-10 nm nanoparticles of Prussian blue analogues incorporating GdIII ions at their periphery revealed longitudinal relaxivities above 40 mM-1 s-1 per GdIII regardless of the nature of the core and the polymer coating. Large T1-weighted contrast enhancements were achieved in addition to a highly efficient photothermal effect and in vivo photoacoustic imaging in tumors.


Assuntos
Ferrocianetos/química , Imagem por Ressonância Magnética/métodos , Nanopartículas/química , Nanomedicina Teranóstica , Animais , Linhagem Celular Tumoral , Meios de Contraste/química , Gadolínio/química , Humanos , Camundongos , Neoplasias/diagnóstico por imagem , Transplante Heterólogo
6.
Int J Nanomedicine ; 14: 7365-7373, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686812

RESUMO

Background: Molecular imaging has generated a great demand to develop targeted contrast agents for MR imaging. Materials and methods: In this study, we synthesized Src homology 2-containing phosphotyrosine phosphatase 2 (SHP2)-targeted and polylactic-co-glycolic acid--based nanoparticles (NPs), which encapsulated perfluoropentane and being chelated with gadolinium (Gd3+) as an efficient molecular probe for targeting MR imaging on thyroid carcinoma. Results: These NPs displayed practical properties and favorable biocompatibility in vitro. Furthermore, they showed abilities to specifically target thyroid cancer and enhance MRI as a contrast agent in both in vitro and in vivo experiments. Conclusion: This novel MR molecular imaging based on this SHP2-targeted contrast agent provides a useful and non-invasive method for the early detection of thyroid carcinoma.


Assuntos
Imagem por Ressonância Magnética , Imagem Molecular , Nanopartículas/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Animais , Apoptose , Linhagem Celular Tumoral , Meios de Contraste , Fluorcarbonetos , Gadolínio/química , Humanos , Camundongos
7.
Nat Commun ; 10(1): 4777, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664017

RESUMO

Early diagnosis and noninvasive detection of liver fibrosis and its heterogeneity remain as major unmet medical needs for stopping further disease progression toward severe clinical consequences. Here we report a collagen type I targeting protein-based contrast agent (ProCA32.collagen1) with strong collagen I affinity. ProCA32.collagen1 possesses high relaxivities per particle (r1 and r2) at both 1.4 and 7.0 T, which enables the robust detection of early-stage (Ishak stage 3 of 6) liver fibrosis and nonalcoholic steatohepatitis (Ishak stage 1 of 6 or 1 A Mild) in animal models via dual contrast modes. ProCA32.collagen1 also demonstrates vasculature changes associated with intrahepatic angiogenesis and portal hypertension during late-stage fibrosis, and heterogeneity via serial molecular imaging. ProCA32.collagen1 mitigates metal toxicity due to lower dosage and strong resistance to transmetallation and unprecedented metal selectivity for Gd3+ over physiological metal ions with strong translational potential in facilitating effective treatment to halt further chronic liver disease progression.


Assuntos
Meios de Contraste/química , Gadolínio/química , Hipertensão Portal/diagnóstico por imagem , Fígado/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Doença Crônica , Diagnóstico Precoce , Humanos
8.
Int J Nanomedicine ; 14: 7879-7889, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576129

RESUMO

Introduction and objective: Precisely and sensitively diagnosing diseases especially early and accurate tumor diagnosis in clinical magnetic resonance (MR) scanner is a highly demanding but challenging task. Gadolinium (Gd) chelate is the most common T 1 magnetic resonance imaging (MRI) contrast agent at present. However, traditional Gd-chelates are suffering from low relaxivity, which hampers its application in clinical diagnosis. Currently, the development of nano-sized Gd based T 1 contrast agent, such as incorporating gadolinium chelate into nanocarriers, is an attractive and feasible strategy to enhance the T 1 contrast capacity of Gd chelate. The objective of this study is to improve the T 1 contrast ability of Gd-chelate by synthesizing nanoparticles (NPs) for accurate and early diagnosis in clinical diseases. Methods: Reverse microemulsion method was used to coat iron oxide (IO) with tunable silica shell and form cores of NPs IO@SiO2 at step one, then Gd-chelate was loaded on the surface of silica-coated iron oxide NPs. Finally, Gd-based silica coating magnetite NPs IO@SiO2-DTPA-Gd was developed and tested the ability to detect tumor cells on the cellular and in vivo level. Results: The r 1 value of IO@SiO2-DTPA-Gd NPs with the silica shell thickness of 12 nm was about 33.6 mM-1s-1, which was approximately 6 times higher than Gd-DTPA, and based on its high T 1 contrast ability, IO@SiO2-DTPA-Gd NPs could effectively detect tumor cells on the cellular and in vivo level. Conclusion: Our findings revealed the improvement of T 1 relaxation was not only because of the increase of molecular tumbling time caused by the IO@SiO2 nanocarrier but also the generated magnetic field caused by the IO core. This nanostructure with high T 1 contrast ability may open a new approach to construct high-performance T 1 contrast agent.


Assuntos
Quelantes/química , Materiais Revestidos Biocompatíveis/química , Gadolínio/química , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/química , Dióxido de Silício/química , Animais , Morte Celular , Meios de Contraste/química , Feminino , Compostos Férricos/química , Gadolínio DTPA/química , Células HeLa , Humanos , Nanopartículas de Magnetita/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Nus , Imagem Molecular
9.
Chem Commun (Camb) ; 55(79): 11924-11927, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31528965

RESUMO

We report a novel ditopic Gd(iii)-based probe selective to zwitterionic amino acid neurotransmitters (ZNTs) crafted for ratiometric MRI imaging. The probe displayed increased binding affinity to ZNTs and non-synchronized concentration-dependent changes of the r1- and r2-relaxivity. Through the application of a T2/T1 weighted MRI strategy, we demonstrated signal enhancement for cooperatively bound glutamate and γ-aminobutyric acid ZNTs over competitive hydrogencarbonate, which remained MR silent.


Assuntos
Aminoácidos/química , Meios de Contraste/química , Complexos de Coordenação/química , Gadolínio/química , Imagem por Ressonância Magnética/métodos , Neurotransmissores/análise , Bicarbonatos/análise , Técnicas Biossensoriais/métodos , Ácido Glutâmico/análise , Ligantes , Compostos Macrocíclicos/química , Peso Molecular , Ácido gama-Aminobutírico/análise
10.
Chem Biodivers ; 16(11): e1900322, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31544357

RESUMO

The synthesis of poly[N,N-bis(3-aminopropyl)glycine] (PAPGly) dendrons Gd-based contrast agents (GdCAs) via an orthogonal protection of the different functional groups and an activation/coupling strategy wherein a specific number of synthetic steps add a generation to the existing dendron has been described. The aim of this protocol is to build up two different generations of dendrons (G-0 or dendron's core, and G-1) with peripheral NH2 groups to conjugate a 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivative and afterwards to chelate with Gd3+ paramagnetic ions. These complexes, which have a well-defined molecular weight, are of relevance to MRI as an attempt to gain higher 1 H relaxivity by slowing down the rotation of molecule compared to monomeric Gd(III) complexes used as contrast agents and to increase the number of paramagnetic centers present in one molecular structure. From the study of their water 1 H longitudinal relaxation rate at different magnetic fields (NMRD, Nuclear Magnetic Relaxation Dispersion) and by evaluating the variable temperature 17 O-NMR data we determined the parameters characterizing the water exchange rate and the rotational correlation time of each complex, both affecting 1 H relaxivity. Furthermore, these two novel PAPGly GdCAs were objects of i) an in vivo study to determine their biodistributions in healthy C57 mice at several time points, and ii) the Dynamic Contrast-Enhanced MRI (DCE-MRI) approach to assess their contrast efficiency measured in the tumor region of C57BL/6 mice transplanted subcutaneously with B16-F10 melanoma cells. The aim of the comparison of these two dendrons GdCAs, having different molecular weights (MW), is to understand how MW and relaxivity may influence the contrast enhancement capabilities in vivo at low magnetic field (1 T). Significant contrast enhancement was observed in several organs (vessel, spleen and liver), already at 5 min post-injection, for the investigated CAs. Moreover, these CAs induced a marked contrast enhancement in the tumor region, thanks to the enhanced permeability retention effect of those macromolecular structures.


Assuntos
Meios de Contraste/química , Gadolínio/química , Melanoma/química , Compostos Organometálicos/química , Animais , Meios de Contraste/síntese química , Meios de Contraste/farmacocinética , Gadolínio/farmacocinética , Humanos , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Melanoma/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Neoplasias Experimentais/química , Neoplasias Experimentais/diagnóstico por imagem , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacocinética , Distribuição Tecidual
11.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547345

RESUMO

Three 1,4,7,10-tetraazacyclododecane-based ligands disubstituted in 1,4-positions with phosphonic acid, phosphonate monoethyl-ester, and H-phosphinic acid pendant arms, 1,4-H4do2p, 1,4-H2do2pOEt, and 1,4-H2Bn2do2pH, were synthesized and their coordination to selected metal ions, Mg(II), Ca(II), Mn(II), Zn(II), Cu(II), Eu(III), Gd(III), and Tb(III), was investigated. The solid-state structure of the phosphonate ligand, 1,4-H4do2p, was determined by single-crystal X-ray diffraction. Protonation constants of the ligands and stability constants of their complexes were obtained by potentiometry, and their values are comparable to those of previously studied analogous 1,7-disubstitued cyclen derivatives. The Gd(III) complex of 1,4-H4do2p is ~1 order of magnitude more stable than the Gd(III) complex of the 1,7-analogue, probably due to the disubstituted ethylenediamine-like structural motif in 1,4-H4do2p enabling more efficient wrapping of the metal ion. Stability of Gd(III)-1,4-H2do2pOEt and Gd(III)-H2Bn2do2pH complexes is low and the constants cannot be determined due to precipitation of the metal hydroxide. Protonations of the Cu(II), Zn(II), and Gd(III) complexes probably takes place on the coordinated phosphonate groups. Complexes of Mn(II) and alkali-earth metal ions are significantly less stable and are not formed in acidic solutions. Potential presence of water molecule(s) in the coordination spheres of the Mn(II) and Ln(III) complexes was studied by variable-temperature NMR experiments. The Mn(II) complexes of the ligands are not hydrated. The Gd(III)-1,4-H4do2p complex undergoes hydration equilibrium between mono- and bis-hydrated species. Presence of two-species equilibrium was confirmed by UV-Vis spectroscopy of the Eu(III)-1,4-H4do2p complex and hydration states were also determined by luminescence measurements of the Eu(III)/Tb(III)-1,4-H4do2p complexes.


Assuntos
Complexos de Coordenação/química , Gadolínio/química , Compostos Heterocíclicos/química , Organofosfonatos/química , Meios de Contraste , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Európio/química , Ligantes , Espectroscopia de Ressonância Magnética , Manganês/química , Ácidos Fosfínicos/química , Potenciometria , Espectrofotometria Ultravioleta , Temperatura Ambiente
12.
Mater Sci Eng C Mater Biol Appl ; 104: 109999, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499945

RESUMO

Chitosan (CTS) and mesoporous calcium silicate (MCS) have been developed for bone defect healing; however, their bone regeneration capacity still does not satisfy the patients with bone diseases. Gadolinium (Gd) is accumulated in human bones, and plays a beneficial role in regulating cell performance and bone regeneration. We firstly constructed Gd-doped MCS/CTS (Gd-MCS/CTS) scaffolds by a lyophilization technology. The interconnected arrangement of CTS films lead to forming macropores by using ice crystals as templates during the lyophilization procedure, and the Gd-MCS nanoparticles dispersed uniformly on the macropore walls. The biocompatible chemical components and hierarchical pores facilitated the attachment and spreading of rat bone marrow-derived mesenchymal stem cells (rBMSCs). Interestingly, the Gd dopants in the scaffolds effectively activated the Wnt/ß-catenin signaling pathway, resulting in excellent cell proliferation and osteogenic differentiation capacities. The osteogenic-related genes such as alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and collagen type1 (COL-1) were remarkably up-regulated by Gd-MCS scaffolds as compared with MCS scaffolds, and their expression levels increased in a positive correlation with Gd doping amounts. Moreover, in vivo rat cranial defect tests further confirmed that Gd-MCS/CTS scaffolds significantly stimulated collagen deposition and new bone formation. The exciting finding suggested the beneficial effects of Gd3+ ions on osteogenic differentiation and new bone regeneration, and Gd-MCS/CTS scaffolds can be employed as a novel platform for bone defect healing.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Compostos de Cálcio/química , Compostos de Cálcio/farmacologia , Quitosana/química , Gadolínio/química , Gadolínio/farmacologia , Silicatos/química , Silicatos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Materiais Biocompatíveis/química , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Engenharia Tecidual/métodos , Tecidos Suporte/química , Regulação para Cima/efeitos dos fármacos
13.
Mater Sci Eng C Mater Biol Appl ; 104: 109972, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499999

RESUMO

The combination of non-invasive fluorescence (FL) and magnetic resonance (MR) imaging can compensate for disadvantages in terms of resolution and sensitivity. However, the preparation of dual-mode probes simultaneously exhibiting strong brightness and high MR response is challenging. A multifunctional nanoprobe was synthesized for targeted photoluminescence (PL) and MR dual-modal imaging. It was obtained by conjugating iridium(III) complexes, gadolinium(III) and the peptide arginine-glycine-aspartate (RGD) onto silica nanoparticles (Ir@SiO2-Gd-RGD NPs). They are highly water soluble, have an average diameter of ~50 nm, and emit strong yellowish green PL (with excitation/emission peaks at 380/572 nm). Simultaneously, the nanoprobes exhibit high MR response with a longitudinal relaxation of 7.16 mM-1 s-1. Instead of simple encapsulation, Ir(III) complexes were covalently conjugated to silica matrix to enhance the chemical and photochemical stability of the nanoprobes. The excellent biocompatibility and PL/MR dual modal imaging capability of the NPs is demonstrated using HeLa cells and mice as models.


Assuntos
Gadolínio/química , Irídio/química , Nanopartículas/química , Dióxido de Silício/química , Animais , Linhagem Celular Tumoral , Meios de Contraste/química , Feminino , Células HeLa , Humanos , Imagem por Ressonância Magnética/métodos , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/química
14.
Nanoscale ; 11(34): 15958-15970, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31418432

RESUMO

Oral drug delivery systems (ODDSs) have attracted considerable attention in relation to orthotopic colon cancer therapy due to certain popular advantages. Unfortunately, their clinical applications are generally limited by the side-effects caused by systemic drug exposure and poor real-time monitoring capabilities. Inspired by the characteristics of pH changes of the gastrointestinal tract (GIT) and specific enzymes secreted by the colonic microflora, we anchored polyacrylic acid (PAA) and chitosan (CS) on Gd3+-doped mesoporous hydroxyapatite nanoparticles (Gd-MHAp NPs) to realize programmed drug release and magnetic resonance imaging (MRI) at the tumor sites. In particular, the grafted PAA, as a pH-responsive switch, could effect controlled drug release in the colon. Further, CS is functionalized as the enzyme-sensitive moiety, which could be degraded by ß-glycosidase in the colon. Gadolinium is a paramagnetic lanthanide element used in chelates, working as a contrast medium agent for an MRI system. Interestingly, after oral administration, CS and PAA could protect the drug-loaded nanoparticles (NPs) against variable physiological conditions in the GIT, allowing the drug to reach the colon tumor sites, preventing premature drug release. Enhanced drug concentrations at the colon tumor sites were achieved via this programmed drug release, which subsequently ameliorated the therapeutic effect. In addition, encapsulating both chemotherapeutic (5-fluorouracil, 5-FU) and targeted therapy drug (gefitinib, Gef) within Gd-MHAp NPs produced a synergistic therapeutic effect. In summary, this study demonstrated that such a novel drug system (Gd-MHAp/5-FU/Gef/CS/PAA NPs) could protect, transport, and program drug release locally within the colonic environment; further, this system exhibited a worthwhile therapeutic effect, providing a promising novel treatment strategy for orthotopic colon cancer.


Assuntos
Neoplasias do Colo , Meios de Contraste , Fluoruracila , Gadolínio , Gefitinibe , Imagem por Ressonância Magnética , Nanopartículas , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/farmacologia , Administração Oral , Animais , Quitosana/química , Quitosana/farmacocinética , Quitosana/farmacologia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Meios de Contraste/química , Meios de Contraste/farmacocinética , Meios de Contraste/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Durapatita/química , Durapatita/farmacocinética , Durapatita/farmacologia , Fluoruracila/química , Fluoruracila/farmacocinética , Fluoruracila/farmacologia , Gadolínio/química , Gadolínio/farmacocinética , Gadolínio/farmacologia , Gefitinibe/química , Gefitinibe/farmacocinética , Gefitinibe/farmacologia , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico
15.
Chem Commun (Camb) ; 55(72): 10784-10787, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31432802

RESUMO

Medical magnetic resonance imaging (MRI) produces high-resolution anatomical images of the human body, but has limited capacity to provide useful molecular information. The light-responsive, liposomal MRI contrast agent described herein could be used to provide an intrinsic theranostic aspect to MRI and enable tracking the distribution and cargo release of drug delivery systems upon light-triggered activation.


Assuntos
Meios de Contraste/química , Sistemas de Liberação de Medicamentos , Gadolínio/química , Luz , Imagem por Ressonância Magnética , Humanos , Lipossomos/química , Estrutura Molecular
16.
Adv Mater ; 31(37): e1901851, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31364218

RESUMO

The development of high-performance contrast agents in magnetic resonance imaging (MRI) has recently received considerable attention, as they hold great promise and potential as a powerful tool for cancer diagnosis. Despite substantial achievements, it remains challenging to develop nanostructure-based biocompatible platforms that can generate on-demand MRI signals with high signal-to-noise ratios and good tumor specificity. Here, the design and synthesis of a new class of nanoparticle-based contrast agents comprising self-assembled NaGdF4 and CaCO3 nanoconjugates is reported. In this design, the spatial confinement of the T1 source (Gd3+ ions) leads to an "OFF" MRI signal due to insufficient interaction between the protons and the crystal lattices. However, when immersed in the mildly acidic tumor microenvironment, the embedded CaCO3 nanoparticles generate CO2 bubbles and subsequently disconnect the nanoconjugate, thus resulting in an "ON" MRI signal. The in vivo performance of these nanoconjugates shows more than 60-fold contrast enhancement in tumor visualization relative to the commercially used contrast agent Magnevist. This work presents a significant advance in the construction of smart MRI nanoprobes ideally suited for deep-tissue imaging and target-specific cancer diagnosis.


Assuntos
Carbonato de Cálcio/química , Meios de Contraste/química , Gadolínio/química , Imagem por Ressonância Magnética/métodos , Nanopartículas/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio
17.
Chemphyschem ; 20(17): 2204-2209, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31298452

RESUMO

The efficiency of MRI contrast agents depends on the relaxation rate enhancement that they can induce at imaging fields. It is well known that, at these fields, large relaxation rates are obtained by binding of gadolinium(III) ions to large molecules. By the same token, the interaction of the gadolinium(III) complexes with macromolecules that are found in biological tissues can be responsible for an increase of the relaxation rate with respect to the value observed in liquids. We investigate here the relaxation enhancement of gadoteridol (Gd-HP-DO3A) in crosslinked hyaluronic acid, taken as model tissue, using fast field-cycling relaxometry. The analysis of the relaxation profiles as a function of the magnetic fields indicates that a sizable increase in the relaxation rates is due to a modest interaction of the contrast agent with the hydrogel and to the slower mobility of the water molecules outside the first-coordination sphere of the gadolinium(III) ion.


Assuntos
Meios de Contraste/química , Compostos Heterocíclicos/química , Ácido Hialurônico/química , Imagem por Ressonância Magnética/métodos , Modelos Biológicos , Compostos Organometálicos/química , Gadolínio/química , Água/química
18.
Future Med Chem ; 11(10): 1157-1175, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31280670

RESUMO

MRI has been recognized as one of the most applied medical imaging techniques in clinical practice. However, the presence of background signal coming from water protons in surrounding tissues makes sometimes the visualization of local contrast agents difficult. To remedy this, fluorine has been introduced as a reliable perspective, thanks to its magnetic properties being relatively close to those of protons. In this review, we aim to give an overall description of fluorine incorporation in contrast agents for MRI. The different kinds of fluorinated probes such as perfluorocarbons, fluorinated dendrimers, polymers and paramagnetic probes will be described, as will their imaging applications such as chemical exchange saturation transfer (CEST) imaging, physico-chemical changes detection, drug delivery, cell tracking and inflammation or tumors detection.


Assuntos
Meios de Contraste/química , Flúor/química , Imagem por Ressonância Magnética/métodos , Animais , Rastreamento de Células/métodos , Dendrímeros/química , Sistemas de Liberação de Medicamentos/métodos , Fluorcarbonetos/química , Gadolínio/química , Halogenação , Humanos , Neoplasias/diagnóstico por imagem , Polímeros/química
19.
Nanoscale ; 11(27): 12973-12982, 2019 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-31263818

RESUMO

Nano-theranostic agents play important roles in the development of therapeutic methods for serious diseases. In this study, novel carbon dots (CDs) L-CD/C-CD were prepared from Gd(iii) salt/complexes, cationic polymers and citric acid in the hope that they would combine the abilities of gene delivery and multi-modal (MR/FL) imaging. The CDs inherited the properties of good water-solubility and positive charge from their precursor polymers. In vitro gene transfection results showed that the CDs have good transfection efficiency and anti-serum ability, especially for L-CD, which has 74 times higher transfection efficiency than PEI 25 kDa in the presence of 10% serum. The CDs exhibited bright fluorescence, which was stable for several days under various pH. Confocal laser scanning microscopy revealed that the CDs could image HeLa cells with blue or green fluorescence well, and realize the monitoring of the gene delivery process. Besides, the CDs showed favorable biocompatibility with excellent performance in longitudinal relaxivity rates (r1) of 11.4 mM-1 s-1 for L-CD and 57.6 mM-1 s-1 for C-CD, which were about 3-15 times higher than that of the clinical Gd reagent Gd-DTPA (3.75 mM-1 s-1). Furthermore, the CDs could perform in vivo tumor-specific MR-imaging more clearly than Gd-DTPA, which is attributed to their suitable particle size and their resulting greater accumulation at tumor site via the EPR effect. This study provides a promising strategy for constructing multi-functional CDs for tumor theranostics.


Assuntos
Carbono , Meios de Contraste , Gadolínio DTPA , Imagem Multimodal , Neoplasias Experimentais/diagnóstico por imagem , Pontos Quânticos/química , Animais , Carbono/química , Carbono/farmacologia , Meios de Contraste/química , Meios de Contraste/farmacologia , Feminino , Gadolínio/química , Gadolínio/farmacologia , Gadolínio DTPA/química , Gadolínio DTPA/farmacologia , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Nanomedicina Teranóstica
20.
Nat Commun ; 10(1): 3184, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320641

RESUMO

Thoracic aortic dissection (TAD) is an aggressive vascular disease that requires early diagnosis and effective treatment. However, due to the particular vascular structure and narrowness of lesion location, there are no effective drug delivery systems for the therapy of TAD. Here, we report a multifunctional delivery nanosystem (TP-Gd/miRNA-ColIV) composed of gadolinium-chelated tannic acid (TA), low-toxic cationic PGEA (ethanolamine-aminated poly(glycidyl methacrylate)) and type IV collagen targeted peptide (ColIV) for targeted nucleic acid therapy, early diagnosis and noninvasive monitoring of TAD. Such targeted therapy with miR-145 exhibits impressive performances in stabilizing the vascular structures and preventing the deterioration of TAD. After the treatment with TP-Gd/miR-145-ColIV, nearly no dissection occurs in the thoracic aortic arches of the mice with TAD model. Moreover, TP-Gd/miRNA-ColIV also demonstrates good magnetic resonance imaging (MRI) ability and can be used to noninvasively monitor the development conditions of TAD.


Assuntos
Aneurisma Dissecante/terapia , Aneurisma da Aorta Torácica/terapia , Sistemas de Liberação de Medicamentos/métodos , Terapia Genética/métodos , MicroRNAs/administração & dosagem , MicroRNAs/uso terapêutico , Aneurisma Dissecante/patologia , Animais , Aneurisma da Aorta Torácica/patologia , Células Cultivadas , Colágeno Tipo IV/química , Gadolínio/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ácidos Polimetacrílicos/química , Taninos/química , Artérias Torácicas/patologia
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