RESUMEN
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.
Asunto(s)
Medios de Contraste , Hígado , Imagen por Resonancia Magnética , Manganeso , Manganeso/química , Hígado/diagnóstico por imagen , Hígado/metabolismo , Imagen por Resonancia Magnética/métodos , Animales , Medios de Contraste/química , Medios de Contraste/síntesis química , Humanos , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/química , Ratones , Complejos de Coordinación/química , Complejos de Coordinación/síntesis químicaRESUMEN
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.
Asunto(s)
Imagen por Resonancia Magnética , Compuestos de Manganeso , Nanopartículas , Óxidos , Terapia Fototérmica , Rutina , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Óxidos/química , Óxidos/farmacología , Animales , Nanopartículas/química , Rutina/química , Rutina/farmacología , Ratones , Humanos , Tamaño de la Partícula , Propiedades de Superficie , Medios de Contraste/química , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Neoplasias/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Metástasis Linfática , Imagen por Resonancia Magnética , Nanopartículas , Porfirinas , Tomografía de Emisión de Positrones , Ganglio Linfático Centinela , Animales , Porfirinas/química , Nanopartículas/química , Ratones , Metástasis Linfática/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Femenino , Ganglio Linfático Centinela/diagnóstico por imagen , Ganglio Linfático Centinela/patología , Humanos , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Ratones Endogámicos BALB C , Línea Celular TumoralRESUMEN
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.