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Manganese(II)-based contrast agents (MBCAs) are potential candidates for gadolinium-free enhanced magnetic resonance imaging (MRI). In this work, a rigid binuclear MBCA (Mn2-PhDTA2) with a zero-length linker was developed via facile synthetic routes, while the other dimer (Mn2-TPA-PhDTA2) with a longer rigid linker was also synthesized via more complex steps. Although the molecular weight of Mn2-PhDTA2 is lower than that of Mn2-TPA-PhDTA2, their T1 relaxivities are similar, being increased by over 71% compared to the mononuclear Mn-PhDTA. In the presence of serum albumin, the relaxivity of Mn2-PhDTA2 was slightly lower than that of Mn2-TPA-PhDTA2, possibly due to the lower affinity constant. The transmetalation reaction with copper(II) ions confirmed that Mn2-PhDTA2 has an ideal kinetic inertness with a dissociation half-life of approximately 10.4 h under physiological conditions. In the variable-temperature 17O NMR study, both Mn-PhDTA and Mn2-PhDTA2 demonstrated a similar estimated q close to 1, indicating the formation of monohydrated complexes with each manganese(II) ion. In addition, Mn2-PhDTA2 demonstrated a superior contrast enhancement to Mn-PhDTA in in vivo vascular and hepatic MRI and can be rapidly cleared through a dual hepatic and renal excretion pattern. The hepatic uptake mechanism of Mn2-PhDTA2 mediated by SLC39A14 was validated in cellular uptake studies.
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Meios de Contraste , Fígado , Imageamento por Ressonância Magnética , Manganês , Manganês/química , Fígado/diagnóstico por imagem , Fígado/metabolismo , Imageamento por Ressonância Magnética/métodos , Animais , Meios de Contraste/química , Meios de Contraste/síntese química , Humanos , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/química , Camundongos , Complexos de Coordenação/química , Complexos de Coordenação/síntese químicaRESUMO
Considerable efforts have been made to develop nanoparticle-based magnetic resonance contrast agents (CAs) with high relaxivity. The prolonged rotational correlation time (τR) induced relaxivity enhancement is commonly recognized, while the effect of the water coordination numbers (q) on the relaxivity of nanoparticle-based CAs gets less attention. Herein, we first investigated the relationship between T1 relaxivity (r1) and q in manganese-based hybrid micellar CAs and proposed a strategy to enhance the relaxivity by increasing q. Hybrid micelles with different ratios of amphiphilic manganese complex (MnL) and DSPE-PEG2000 were prepared, whose q values were evaluated by Oxygen-17-NMR spectroscopy. Micelles with lower manganese doping density exhibit increased q and enhanced relaxivity, corroborating the conception. In vivo sentinel lymph node (SLN) imaging demonstrates that DSPE-PEG/MnL micelles could differentiate metastatic SLN from inflammatory LN. Our strategy makes it feasible for relaxivity enhancement by modulating q, providing new approaches for the structural design of high-performance hybrid micellar CAs.
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Micelas , Água , Manganês/química , Linfografia , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Meios de Contraste/químicaRESUMO
MRI contrast agents with high kinetic stability and relaxivity are the key objectives in the field. We previously reported that Gd-DOTA backboned-bound branched polymers possess high kinetic stability and significantly increased T1 relaxivity than traditional branched polymer contrast agents. In this work, non-PEGylated and PEGylated amphiphilic Gd-DOTA backboned-bound branched polymers [P(GdDOTA-C6), P(GdDOTA-C10), mPEG-P(GdDOTA-C6), and mPEG-P(GdDOTA-C10)] were obtained by sequential introduction of rigid carbon chains (1,6-hexamethylenediamine or 1,10-diaminodecane) and mPEG into the structure of Gd-DOTA backboned-bound branched polymers. It is found that the introduction of both rigid carbon chains, especially the longer one, and mPEG can increase the kinetic stability and T1 relaxivity of Gd-DOTA backboned-bound branched polymers. Among them, mPEG-P(GdDOTA-C10) possesses the highest kinetic stability (significantly higher than those of linear Gd-DTPA and cyclic Gd-DOTA-butrol) and T1 relaxivity (42.9 mM-1 s-1, 1.5 T), 11 times that of Gd-DOTA and 1.4 times that of previously reported Gd-DOTA backboned-bound branched polymers. In addition, mPEG-P(GdDOTA-C10) showed excellent MRA effect in cardiovascular and hepatic vessels at a dose (0.025 or 0.05 mmol Gd/kg BW) far below the clinical range (0.1-0.3 mmol Gd/kg BW). Overall, effective branched-polymer-based contrast agents can be obtained by a strategy in which rigid carbon chains and PEG were introduced into the structure of Gd-DOTA backbone-bound branched polymers, resulting in excellent kinetic stability and enhanced T1 relaxivity.
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Compostos Organometálicos , Polímeros , Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Polietilenoglicóis , Compostos Organometálicos/química , CarbonoRESUMO
The unsatisfactory performance of current gadolinium chelate based T1 contrast agents (CAs) for magnetic resonance imaging (MRI) stimulates the search for better alternatives. Herein, we report a new strategy to substantially improve the capacity of nanoparticle-based T1 CAs by exploiting the photoinduced superhydrophilic assistance (PISA) effect. As a proof of concept, we synthesized citrate-coated Gd-doped TiO2 ellipsoidal nanoparticles (GdTi-SC NPs), whose r1 increases significantly upon UV irradiation. The reduced water contact angle and the increased number of surface hydroxyl groups substantiate the existence of the PISA effect, which considerably promotes the efficiency of paramagnetic relaxation enhancement (PRE) and thus the imaging performance of GdTi-SC NPs. In vivo MRI of SD rats with GdTi-SC NPs further demonstrates that GdTi-SC NPs could serve as a high-performance CA for sensitive imaging of blood vessels and accurate diagnosis of vascular lesions, indicating the success of our strategy.
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Gadolínio , Nanopartículas , Animais , Meios de Contraste/farmacologia , Imageamento por Ressonância Magnética/métodos , Ratos , Ratos Sprague-Dawley , TitânioRESUMO
Manganese oxide nanoparticles (MONs)-based contrast agents have attracted increasing attention for magnetic resonance imaging (MRI), attributed to their good biocompatibility and advantageous paramagnetism. However, conventional MONs have poor imaging performance due to low T1 relaxivity. Additionally, their lack of tumor-targeting theranostics capabilities and complex synthesis pathways have impeded clinical applications. Rutin (Ru) is an ideal tumor-targeted ligand that targets glucose transporters (GLUTs) overexpressed in various malignant tumors, and exhibits photothermal effects upon chelation with metal ions. Herein, a series of Ru-coated MONs (Ru/MnO2) were synthesized using a straightforward, rapid one-step process. Specifically, Ru/MnO2-5, with the smallest crystal size of approximately 4 nm, exhibits the highest T1 relaxivity (33.3 mM-1s-1 at 1.5 T, surpassing prior MONs) along with notable stability, photothermal efficacy, and tumor-targeting ability. Furthermore, Ru/MnO2-5 shows promise in MRI and photothermal therapy of H22 tumors owing to its superior GLUTs-mediated tumor-targeting capability.
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Imageamento por Ressonância Magnética , Compostos de Manganês , Nanopartículas , Óxidos , Terapia Fototérmica , Rutina , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Óxidos/química , Óxidos/farmacologia , Animais , Nanopartículas/química , Rutina/química , Rutina/farmacologia , Camundongos , Humanos , Tamanho da Partícula , Propriedades de Superfície , Meios de Contraste/química , Sobrevivência Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Neoplasias/tratamento farmacológicoRESUMO
Diagnosing of lymph node metastasis is challenging sometimes, and multimodal imaging offers a promising method to improve the accuracy. This work developed porphyrin-based nanoparticles (68Ga-F127-TAPP/TCPP(Mn) NPs) as PET/MR dual-modal probes for lymph node metastasis imaging by a simple self-assembly method. Compared with F127-TCPP(Mn) NPs, F127-TAPP/TCPP(Mn) NPs synthesized by amino-porphyrins (TAPP) doping can not only construct PET/MR bimodal probes but also improve the T1 relaxivity (up to 456%). Moreover, T1 relaxivity can be adjusted by altering the molar ratio of TAPP/TCPP(Mn) and the concentration of F127. However, a similar increase in T1 relaxivity was not observed in the F127-TCPP/TCPP(Mn) NPs, which were synthesized using carboxy-porphyrins (TCPP) doping. In a breast cancer lymph node metastasis mice model, subcutaneous injection of 68Ga-F127-TAPP/TCPP(Mn) NPs through the hind foot pad, the normal lymph nodes and metastatic lymph nodes were successfully distinguished based on the difference of PET standard uptake values and MR signal intensities. Furthermore, the dark brown F127-TAPP/TCPP(Mn) NPs demonstrated the potential for staining and mapping lymph nodes. This study provides valuable insights into developing and applying PET/MR probes for lymph node metastasis imaging.
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Metástase Linfática , Imageamento por Ressonância Magnética , Nanopartículas , Porfirinas , Tomografia por Emissão de Pósitrons , Linfonodo Sentinela , Animais , Porfirinas/química , Nanopartículas/química , Camundongos , Metástase Linfática/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Feminino , Linfonodo Sentinela/diagnóstico por imagem , Linfonodo Sentinela/patologia , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Camundongos Endogâmicos BALB C , Linhagem Celular TumoralRESUMO
Carbohydrates have emerged as promising candidates for immunomodulation, however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles, comparing to mannose and galactose. In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK, and STAT1 signaling pathways. Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy.
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Nanopartículas , Receptor 4 Toll-Like , Camundongos , Animais , Receptor 4 Toll-Like/metabolismo , Macrófagos/metabolismo , Nanopartículas/química , NF-kappa B/metabolismo , Transdução de SinaisRESUMO
Effective vascular and hepatic enhancement and better safety are the key drivers for exploring gadolinium-free hepatobiliary contrast agents. Herein, a facile strategy proposes that the high lipophilicity may be favorable to enhancing sequentially vascular and hepatobiliary signal intensity based on the structure-activity relationship that both hepatic uptake and interaction with serum albumins partly depend on lipophilicity. Therefore, 11 newly synthesized derivatives of manganese o-phenylenediamine-N,N,N',N'-tetraacetic acid (MnLs) were evaluated as vascular and hepatobiliary agents. The maximum signal intensities of the heart, liver, and kidneys were strongly correlated with log P, a key indicator of lipophilicity. The most lipophilic agent, MnL6, showed favorable relaxivity when binding with serum albumin, good vascular enhancement, rapid excretion, and reliable hepatobiliary phases comparable to a classic hepatobiliary agent, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) for in vivo liver tumor imaging. Inhibition experiments confirmed the hepatic targeting of MnL6 is mediated by organic anion-transporting polypeptides.
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Meios de Contraste , Neoplasias Hepáticas , Humanos , Meios de Contraste/metabolismo , Manganês , Gadolínio DTPA/metabolismo , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
Rationale: Magnetic nanoparticles (MNPs) are the most used inorganic nanoparticles in clinics with therapeutic and imaging functions, but the inefficient magneto-thermal conversion efficiency, fast leakage, and uneven distribution impair their imaging sensitivity and therapeutic efficacy in tumors. Methods: Herein, we rationally designed a system containing pH-controllable charge-reversible MNPs (M20@DPA/HA) and negatively charged MMPs with different sizes (M5 and M20), which could induce intracellular aggregation. The dynamic hydrazone bonds with pH controllability were formed by the surface hydrazides on MNPs and aldehydes of hyaluronic acid (HA). Under the acidic pH, intracellular aggregation of the complex composed by M20@DPA/HA and M5 (M5&20), or M20@DPA/HA and M20 (M20&20) were investigated. In addition, the magnetic hyperthermia therapy (MHT) efficiency of tumor cells, tumor-associated macrophages polarization, giant cells formation and immune activation of tumor microenvironment were explored via a series of cell and animal model experiments. Results: Through physical and chemical characterization, the aggregation system (M20&20) exhibited a remarkable 20-fold increase in magnetothermal conversion efficiency compared to individual MNPs, together with enhanced penetration and retention inside the tumor tissues. In addition, it could promote immune activation, including repolarization of tumor-associated macrophages, as well as the formation of giant cells for T cell recruitment. As a result, the M20&20 aggregation system achieved a high degree of inhibition in 4T1 mouse mammary tumor model, with little tumor growth and metastasis after magnetic hyperthermia therapy. Conclusions: A controlled intracellular aggregation system was herein developed, which displayed an aggregation behavior under the acidic tumor microenvironment. The system significantly enhanced MHT effect on tumor cells as well as induced M1 polarization and multinucleated giant cells (MGC) formation of TAM for immune activation. This controlled aggregation system achieved barely tumor growth and metastasis, showing a promising strategy to improve MNPs based MHT on deteriorate cancers.
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Hipertermia Induzida , Nanopartículas de Magnetita , Neoplasias , Camundongos , Animais , Hipertermia Induzida/métodos , Nanopartículas de Magnetita/uso terapêutico , Nanopartículas de Magnetita/química , Neoplasias/terapia , Ácido Hialurônico , Fenômenos Magnéticos , Microambiente TumoralRESUMO
Early diagnosis of osteoarthritis (OA) is critical for effective cartilage repair. However, lack of blood vessels in articular cartilage poses a barrier to contrast agent delivery and subsequent diagnostic imaging. To address this challenge, we proposed to develop ultra-small superparamagnetic iron oxide nanoparticles (SPIONs, 4 nm) that can penetrate into the matrix of articular cartilage, and further modified with the peptide ligand WYRGRL (particle size, 5.9 nm), which allows SPIONs to bind to type II collagen in the cartilage matrix and increase the retention of probes. Type II collagen in the cartilage matrix is gradually lost with the progression of OA, consequently, the binding of peptide-modified ultra-small SPIONs to type II collagen in the OA cartilage matrix is less, thus presenting different magnetic resonance (MR) signals in OA group from the normal ones. By introducing the AND logical operation, damaged cartilage can be differentiated from the surrounding normal tissue on T1 and T2 AND logical map of MR images, and this was also verified in histology studies. Overall, this work provides an effective strategy for delivering nanosized imaging agents to articular cartilage, which could potentially be used to diagnosis joint-related diseases such as osteoarthritis.
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Precise diagnosis of lymph node metastasis is important for therapeutic regimen planning, prognosis analysis and probably better outcomes for cancer patients. In this work, 68Ga-labeled amphiphilic alternating copolymers nanoparticles with different rigid ligands were synthesized as positron emission tomography (PET) probes for lymph node metastasis imaging. The labeling efficiency and stability of nanoparticles was improved with increased rigidity of coordination unit. PU(68Ga-L-MDI-PEG) nanoparticles (PU(68Ga-L-MDI-PEG) NPs) with the strongest rigidity of coordination unit exhibited the lowest critical micelle concentration, the best 68Ga labeling efficiency and stability. During in vivo lymph node metastasis imaging, PU(68Ga-L-MDI-PEG) NPs led to different accumulations in normal lymph nodes (N-LN) and tumor metastasized sentinel lymph nodes (T-SLN), which resulted in different PET signal presentation, making it feasible to differentiate N-LN from T-SLN. In comparison, small molecule probe 68GaL had poor lymph node accumulation, not only making it difficult to find lymph nodes on PET/computed tomography scan, but also tough to distinguish N-LN from metastatic ones. Overall, this work provides a reference for design of 68Ga labeled polymeric nanoparticles with high chelation efficiency and stability, as sensitive PET probes for lymph node imaging.
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Photodynamic therapy (PDT) still faces great challenges with suitable photosensitizers, oxygen supply, and reactive oxygen species (ROS) accumulation, especially in the tumor microenvironment, feathering hypoxia, and high glucose metabolism. Herein, a carbon dots (CDs)-based bifunctional nanosystem (MnZ@Au), acting as photosensitizer and nanozyme with cascading glucose oxidase (GOx)- and catalase (CAT)-like reactivity, was developed for improving hypoxia and regulating glucose metabolism to enhance PDT. The MnZ@Au was constructed using Mn-doped CDs (Mn-CDs) as a core and zeolitic imidazolate framework-8 (ZIF-8) as a shell to form a hybrid (MnZ), followed by anchoring ultrasmall Au nanoparticles (AuNPs) onto the surface of MnZ through the ion exchange and in situ reduction methods. MnZ@Au catalyzed glucose consumption and oxygen generation by cascading GOx- and CAT-like nanozyme reactions, which was further enhanced by its own photothermal properties. In vitro and in vivo studies also confirmed that MnZ@Au greatly improved CDs penetration, promoted ROS accumulation, and enhanced PDT efficacy, leading to efficient tumor growth inhibition in the breast tumor model. Besides, MnZ@Au enabled photoacoustic (PA) imaging to provide a mapping of Mn-CDs distribution and oxygen saturation, showing the real-time catalytic process of MnZ@Au in vivo. 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging also validated the decreased glucose uptake in tumors treated by MnZ@Au. Therefore, the integrated design provided a promising strategy to utilize and regulate the tumor microenvironment, promote penetration, enhance PDT, and finally prevent tumor deterioration.
Assuntos
Nanopartículas Metálicas , Fotoquimioterapia , Humanos , Ouro/farmacologia , Espécies Reativas de Oxigênio , Glicólise , Hipóxia , Oxigênio , Carbono/farmacologia , Glucose , Glucose OxidaseRESUMO
The localization and differential diagnosis of the sentinel lymph nodes (SLNs) are particularly important for tumor staging, surgical planning and prognosis. In this work, kinetically inert manganese (II)-based hybrid micellar complexes (MnCs) for magnetic resonance imaging (MRI) were developed using an amphiphilic manganese-based chelate (C18-PhDTA-Mn) with reliable kinetic stability and self-assembled with a series of amphiphilic PEG-C18 polymers of different molecular weights (C18En, n = 10, 20, 50). Among them, the probes composed by 1:10 mass ratio of manganese chelate/C18En had slightly different hydrodynamic particle sizes with similar surface charges as well as considerable relaxivities (â¼13 mM-1 s-1 at 1.5 T). In vivo lymph node imaging in mice revealed that the MnC MnC-20 formed by C18E20 with C18-PhDTA-Mn at a hydrodynamic particle size of 5.5 nm had significant signal intensity brightening effect and shortened T1 relaxation time. At an imaging probe dosage of 125 µg Mn/kg, lymph nodes still had significant signal enhancement in 2 h, while there is no obvious signal intensity alteration in non-lymphoid regions. In 4T1 tumor metastatic mice model, SLNs showed less signal enhancement and smaller T1 relaxation time variation at 30 min post-injection, when compared with normal lymph nodes. This was favorable to differentiate normal lymph nodes from SLN under a 3.0-T clinical MRI scanner. In conclusion, the strategy of developing manganese-based MR nanoprobes was useful in lymph node imaging.
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Compared to traditional branched polymers with Gd(III) chelates conjugated on their surface, branched polymers with Gd(III) chelates as the internal skeleton are considered to be a reasonable strategy for preparing efficient magnetic resonance imaging contrast agents. Herein, the Gd(III) ligand DOTA was chosen as the internal skeleton; four different molecular weights (3.5, 5.3, 8.6, and 13.1 kDa) and degrees of branching poly-DOTA branched polymers (P1, P2, P3, and P4) were synthesized by a simple "A2 + B4"-type one-pot polymerization. The Gd(III) chelates of these poly-DOTA branched polymers (P1-Gd, P2-Gd, P3-Gd, and P4-Gd) display excellent kinetic stability, which is significantly higher than those of linear Gd-DTPA and cyclic Gd-DOTA-butrol and slightly lower than that of cyclic Gd-DOTA. The T1 relaxivities of P1-Gd, P2-Gd, P3-Gd, and P4-Gd are 29.4, 38.7, 44.0, and 47.9 Gd mM-1 s-1, respectively, at 0.5 T, which are about 6-11 times higher than that of Gd-DOTA (4.4 Gd mM-1 s-1). P4-Gd was selected for in vivo magnetic resonance angiography (MRA) because of its high kinetic stability, T1 relaxivity, and good biosafety. The results showed excellent MRA effect, sensitive detection of vascular stenosis, and prolonged observation window as compared to Gd-DOTA. Overall, Gd(III) chelates of poly-DOTA branched polymers are good candidates of MRI probes, providing a unique design strategy in which Gd chelation can occur at both the interior and surface of the poly-DOTA branched polymers, resulting in excellent relaxivity enhancement. In vivo animal MRA studies of the probe provide possibilities in discovering small vascular pathologies.
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Compostos Organometálicos , Polímeros , Animais , Angiografia por Ressonância Magnética , Gadolínio , Imageamento por Ressonância Magnética/métodos , Meios de Contraste , QuelantesRESUMO
Gadolinium (Gd)-based contrast agents (CAs) for clinical magnetic resonance imaging are facing the problems of low longitudinal relaxivity (r1) and toxicity caused by gadolinium deposition. Manganese-based small molecule complexes and manganese oxide nanoparticles (MONs) are considered as potential alternatives to Gd-based CAs due to their better biocompatibility, but their relatively low r1 values and complicated synthesis routes slow down their clinical translation. Herein, we presented a facile one-step co-precipitation method to prepare MONs using poly(acrylic acid) (PAA) as a coating agent (MnO2/PAA NPs), which exhibited good biocompatibility and high r1 values. A series of MnO2/PAA NPs with different particle sizes were prepared and the relationship between the particle size and r1 was studied, revealing that the MnO2/PAA NPs with a particle size of 4.9 nm exhibited higher r1. The finally obtained MnO2/PAA NPs had a high r1 value (29.0 Mn mM-1 s-1) and a low r2/r1 ratio (1.8) at 1.5 T, resulting in a strong T1 contrast enhancement. In vivo magnetic resonance angiography with Sprague-Dawley (SD) rats further proved that the MnO2/PAA NPs showed better angiographic performance at low-dosage administration than commercial Gadovist® (Gd-DO3A-Butrol). Moreover, the MnO2/PAA NPs could be rapidly cleared out after imaging, which effectively minimized the toxic side effects. The MnO2/PAA NPs are promising candidates for MR imaging of vascular diseases.
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Nanopartículas , Óxidos , Ratos , Animais , Angiografia por Ressonância Magnética , Compostos de Manganês , Gadolínio , Ratos Sprague-Dawley , Meios de Contraste , Imageamento por Ressonância Magnética/métodosRESUMO
Macrophage autophagy is a common biological response triggered by nanomaterials, which is closely related to the regulation of inflammation. Superparamagnetic iron oxide (SPIO) nanoparticles have been used for study of autophagy response due to their broad biomedical applications. However, few reports have focused on how to regulate the macrophage autophagy response induced by SPIO nanoparticles. In this study, SPIO nanoparticles grafted with carboxyl groups were synthesized and for the comparison of macrophage autophagy with unmodified nanoparticles. The study on the correlation between autophagy and inflammation induced by the two kinds of SPIO nanoparticles was also included, and the one that grafted with carboxyl groups shows a reduction of autophagy and thereby caused a milder inflammatory response. We proposed that the increased amount of albumin adsorption on the surface of carboxylated SPIO nanoparticles, a protein previously proven to attenuate autophagy, can be considered an important reason for reducing autophagy and inflammation. In general, the carboxyl modification of SPIO nanoparticles has been demonstrated to reduce inflammation by inhibiting macrophage autophagy, which may provide some insights for the design of nanomaterials in the future.
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Diagnosis of sentinel lymph node (SLN) metastasis and its status are key parameters for predicting overall disease prognosis. In this work, Pluronic F127 stabilized ICG/tetra(4-carboxyphenyl)porphyrin-Mn(III) (TCPP(Mn)) nanoparticles (F127-ICG/Mn NPs) as fluorescent/magnetic resonance (FL/MR) dual-modality probes were prepared. The application of F127-ICG/Mn NPs in SLN imaging was mainly evaluated from two perspectives: the difference between the normal LN and the metastatic SLN and the difference between micrometastasis and macrometastasis. Normal and metastatic SLNs and micro- and macro-SLN metastasis were successfully distinguished through fluorescence and MR imaging with the help of F127-ICG/Mn NPs. In contrast, for the ICG group, the micro- and macro-SLN metastasis status could not be differentiated by fluorescence imaging. Besides, the lymph nodes can be stained green by the F127-ICG/Mn NPs and clearly visualized by the naked eye. In general, F127-ICG/Mn NPs demonstrated the potential of the preoperative diagnosis of SLN metastasis and its status, as well as intraoperative navigation by green-stained SLN and NIR FL imaging. This work provides a reference for developing multimodal nanoparticles for SLN metastasis diagnosis.
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Nanopartículas , Porfirinas , Linfonodo Sentinela , Humanos , Linfonodo Sentinela/diagnóstico por imagem , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Biópsia de Linfonodo Sentinela/métodos , Manganês , Verde de Indocianina , Imagem Óptica/métodos , Corantes Fluorescentes , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância MagnéticaRESUMO
Currently, the most commonly used clinical magnetic resonance imaging (MRI) contrast agents, Gd(III) chelates, have been found to be associated with nephrogenic systemic fibrosis (NSF) in renally compromised patients. Toxicity concerns related to Gd(III)-based agents prompted intensive research toward the development of safe, efficient, and long-cycle non-Gd contrast agents. Herein, three amphiphilic polymeric manganese (Mn) ligands (mPEG1k-P(L-a-HMDI)-mPEG1k, mPEG2k-P(L-a-HMDI)-mPEG2k and mPEG4k-P(L-a-HMDI)-mPEG4k) were synthesized, and then end-capped respectively with different molecular weights of polyethylene glycol monomethyl ether (mPEG 1 kD, 2 kD and 4 kD) to obtain amphiphilic polymer Mn ligands. After being chelated with Mn(II), these amphiphilic polymer Mn complexes show significantly higher T1 relaxivity than the small molecule Mn complex (MnL) at 0.5 T, 1.5 T and 3.0 T magnetic fields, respectively. Then, mPEG2k-P(MnL-a-HMDI)-mPEG2k with relatively high T1 relaxivities (23.2, 14.4 and 9.7 mM-1s-1 at 0.5 T, 1.5 T and 3.0 T, respectively), low CMC (4.7 mg L-1), reasonable size (48 nm) and excellent stability among these three polymer Mn complexes was selected for in vivo MR imaging of vascular vessels. The results suggest that mPEG2k-P(MnL-a-HMDI)-mPEG2k has an excellent and relatively long time-window vascular enhancement effect even at a low dose of 0.05 mmol Mn kg-1 BW, and could play a role in the diagnosis of vascular diseases (0.1 mmol Mn kg-1 BW). Therefore, mPEG2k-P(MnL-a-HMDI)-mPEG2k may be considered as a potential blood pool contrast agent.
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Meios de Contraste , Manganês , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , PolietilenoglicóisRESUMO
Magnetic resonance imaging (MRI) has been widely used for disease diagnosis because it can noninvasively obtain anatomical details of various diseases through accurate contrast between soft tissues. Over one-third of MRI examinations are performed with the assistance of contrast agents. Traditional contrast agents typically display an unchanging signal, thus exhibiting relatively low sensitivity and poor specificity. Currently, advances in stimulus-responsive contrast agents which can alter the relaxation signal in response to a specific change in their surrounding environment provide new opportunities to overcome such limitation. The signal changes based on stimulus also reflects the physiological and pathological conditions of the site of interests. In this review, how to design stimulus-responsive nanoparticle MRI contrast agents from the perspective of theory and surface design is comprehensively discussed. Key structural features including size, clusters, shell features, and surface properties are used for tuning the T1 and T2 relaxation properties. The reversible or non-reversible signal changes highlight the contrast agents have undergone structural changes based on certain stimulus, as an indication for disease diagnosis or therapeutic efficacy.
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Meios de Contraste , Nanopartículas , Imageamento por Ressonância MagnéticaRESUMO
Osteoporosis is a skeletal disorder resulted in significant structural and functional changes, arousing a wide concern for the high prevalence and cost. Imbalance between osteoclastogenesis and osteogenesis have been verified as a main pathology etiology and considered an efficient therapy target in both clinical and pre-clinical studies. In recent years, inorganic nanomaterials have shown provable activities on osteoclastogenesis inhibition and osteogenesis promotion, respectively. Hence, in this study, a class of hydroxyapatite coated superparamagnetic iron oxide nanoparticles (SPIO@HA) were developed with a core-shell structure for targeting both osteoclastogenesis and osteogenesis. The optimal ratio of SPIO@15HA (Fe/Ca = 1:15, mol/mol) was screened to obtain dual function for inducing both bone formation and preventing bone resorption. The obtained nanocomposites significantly prevented the bone loss of ovariectomized (OVX) mice and increased bone mineral density (BMD) by 9.4%, exhibiting high bone accumulation in magnetic resonance imaging evaluation and reasonable biosafety profile. The mechanism study revealed that SPIO@15HA can suppress bone marrow monocyte derived osteoclast differentiation through TRAF6-p62-CYLD signaling complex regulation. Meanwhile, it could activate MSC osteogenic differentiation by TGF-ß, PI3K-AKT and calcium signaling pathway regulation. Moreover, incubation of SPIO@15HA with MSC resulted in several cytokines overexpression such as osteoprotegerin (OPG), CSF2, CCL2 etc., which are responsible for maintaining the bone remodeling balance. The dual function of as-prepared SPIO@15HA may find a new way for designing of inorganic components containing core/shell nanomaterials for osteoporosis treatment.