RESUMEN
Glutathione (GSH)-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn2+ with threshold GSH concentration of ≈ 0.12 mm for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH-relevant cisplatin resistance during chemotherapy. Upon efficient up-regulation of extracellular GSH in tumor via exogenous injection, the relaxivity-silent interstitial nanoprobe remarkably evolves into Mn2+ that are further captured/retained and re-activated into ultrahigh-relaxivity-capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off-targeted nanoprobe in the form of Mn2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin-mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.
Asunto(s)
Albúminas , Glutatión , Imagen por Resonancia Magnética , Nanopartículas del Metal , Sondas Moleculares , Neoplasias , Glutatión/administración & dosificación , Glutatión/farmacocinética , Glutatión/farmacología , Sondas Moleculares/administración & dosificación , Sondas Moleculares/farmacocinética , Sondas Moleculares/farmacología , Albúminas/administración & dosificación , Albúminas/farmacocinética , Albúminas/farmacología , Imagen por Resonancia Magnética/métodos , Medios de Contraste/administración & dosificación , Medios de Contraste/farmacocinética , Medios de Contraste/farmacología , Aumento de la Imagen/métodos , Holografía/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiología , Nanopartículas del Metal/administración & dosificación , Transferrina/administración & dosificación , Transferrina/farmacocinética , Transferrina/farmacología , Distribución Tisular , Células A549 , Humanos , Animales , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Cisplatino/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologíaRESUMEN
Thioredoxin-interacting protein (TXNIP) is involved in multiple disease-associated functions related to oxidative stress, especially by inhibiting the anti-oxidant- and thiol-reducing activity of thioredoxin (TXN). Shiga-Y5 (SY5), a fluorine-19 magnetic resonance probe for detecting amyloid-ß deposition in the brain, previously showed therapeutic effects in a mouse model of Alzheimer's disease; however, the mechanism of action of SY5 remains unclear. SY5 passes the blood-brain barrier and then undergoes hydrolysis to produce a derivative, Shiga-Y6 (SY6), which is a TXNIP-negative regulator. Therefore, this study investigates the therapeutic role of SY5 as the prodrug of SY6 in the thioredoxin system in the brain of a mouse model of Alzheimer's disease. The intraperitoneal injection of SY5 significantly inhibited TXNIP mRNA (p = 0.0072) and protein expression (p = 0.0143) induced in the brain of APP/PS1 mice. In contrast, the levels of TXN mRNA (p = 0.0285) and protein (p = 0.0039) in the brain of APP/PS1 mice were increased after the injection of SY5. The ratio of TXN to TXNIP, which was decreased (p = 0.0131) in the brain of APP/PS1 mice, was significantly increased (p = 0.0072) after the injection of SY5. These results suggest that SY5 acts as a prodrug of SY6 in targeting the thioredoxin system and could be a potential therapeutic compound in oxidative stress-related diseases in the brain.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Proteínas Portadoras/antagonistas & inhibidores , Curcumina/farmacología , Modelos Animales de Enfermedad , Sondas Moleculares/farmacología , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Curcumina/administración & dosificación , Curcumina/análogos & derivados , Flúor , Inyecciones Intraperitoneales , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Sondas Moleculares/administración & dosificación , Sondas Moleculares/química , Estructura MolecularRESUMEN
BACKGROUND Albumin level does not precisely reflect nutritional status. We aimed to investigate the impact of a nutrition intervention on hemodialysis patients by use of fluorescence-based plasma albumin (FPA) detection. MATERIAL AND METHODS Eighty patients underwent maintenance hemodialysis for more than half a year and had a mean albumin <3.5 g/dL for over 3 months. The subjects were randomly divided into either a Control Group (CG) or an Intervention Group (IG). The IG received nutritional supplementation, and the CG group received routine nutritional support for 12 months. FPA and plasma albumin (PA) concentrations were measured. The fluorescence probe 1,3-Dichloro-7-hydroxy-9,9-dimethyl-2(9H)-acridone methyl biphenyl benzoate was used in FPA detection. Quality of life was estimated using WHOQOL-BREF (Quality of Life Scale developed through the World Health Organization), the 36-Item Short-Form Survey (SF-36), and the 6-minute walking test (6MWT). RESULTS After a 6-month and a 12-month intervention, PA and FPA concentrations increased, and the increase in FPA concentration was higher than that of PA in the IG group (P<0.05). Comparatively, the parameters of quality of life and 6MWT were improved in the IG group (P<0.05) but there were only minor changes in the CG group (P>0.05). There is an obvious association between the changes in FPA concentration and the parameters of quality of life and 6MWT but not PA. CONCLUSIONS Use of the fluorescence probe improves the detection sensitivity of plasma albumin and provides a potential method to assess clinical outcomes in hemodialysis patients.
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Fallo Renal Crónico/terapia , Desnutrición/diagnóstico , Atención de Enfermería/métodos , Apoyo Nutricional/métodos , Albúmina Sérica Humana/análisis , Adulto , Femenino , Fluorescencia , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Desnutrición/sangre , Desnutrición/etiología , Desnutrición/terapia , Persona de Mediana Edad , Sondas Moleculares/administración & dosificación , Sondas Moleculares/química , Calidad de Vida , Diálisis Renal/efectos adversos , Albúmina Sérica Humana/química , Resultado del Tratamiento , Prueba de PasoRESUMEN
The glypican-3 (GPC3) receptor is a membrane protein that is highly expressed in tumor tissues but rarely expressed in the normal liver and can be used as a target for early diagnosis of hepatocellular carcinoma (HCC). Herein, we developed a GPC3-targeted 99mTc-labeled probe for SPECT imaging in HCC. 99mTc-HPG was rapidly radiosynthesized within 20 min with an excellent radiochemical purity (>98%), possessing good stability. Results from in vitro cell binding assays indicated that the binding specificity of 99mTc-HPG to GPC3-positive HepG2 cells was acceptable. For SPECT/CT imaging, the HepG2 tumors were clearly visualized with the highest tumor/muscle ratio (11.55 ± 0.54) at 1 h post-injection, and the tumor uptake of 99mTc-HPG reduced from 2.99 ± 0.15 to 1.17 ± 0.09% ID/g in the blocking study. Convenient preparation, excellent GPC3 specificity in HCC, rapid clearance from normal organs, and good biosafety profiles of 99mTc-HPG warrant further investigations for clinical translation.
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Carcinoma Hepatocelular/diagnóstico , Glipicanos/metabolismo , Neoplasias Hepáticas/diagnóstico , Radiofármacos/administración & dosificación , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Carcinoma Hepatocelular/patología , Femenino , Células Hep G2 , Humanos , Neoplasias Hepáticas/patología , Ratones , Imagen Molecular/métodos , Sondas Moleculares/administración & dosificación , Sondas Moleculares/farmacocinética , Compuestos de Organotecnecio/administración & dosificación , Compuestos de Organotecnecio/farmacocinética , Radiofármacos/farmacocinética , Tecnecio , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nanoparticle internalisation is crucial for the precise delivery of drug/genes to its intracellular targets. Conventional quantification strategies can provide the overall profiling of nanoparticle biodistribution, but fail to unambiguously differentiate the intracellularly bioavailable particles from those in tumour intravascular and extracellular microenvironment. Herein, we develop a binary ratiometric nanoreporter (BiRN) that can specifically convert subtle pH variations involved in the endocytic events into digitised signal output, enabling the accurately quantifying of cellular internalisation without introducing extracellular contributions. Using BiRN technology, we find only 10.7-28.2% of accumulated nanoparticles are internalised into intracellular compartments with high heterogeneity within and between different tumour types. We demonstrate the therapeutic responses of nanomedicines are successfully predicted based on intracellular nanoparticle exposure rather than the overall accumulation in tumour mass. This nonlinear optical nanotechnology offers a valuable imaging tool to evaluate the tumour targeting of new nanomedicines and stratify patients for personalised cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Portadores de Fármacos/análisis , Imagen Molecular/métodos , Nanopartículas/análisis , Neoplasias/tratamiento farmacológico , Animales , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Femenino , Colorantes Fluorescentes/química , Humanos , Microscopía Intravital , Ratones , Sondas Moleculares/administración & dosificación , Sondas Moleculares/análisis , Sondas Moleculares/química , Nanopartículas/administración & dosificación , Nanopartículas/química , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Imagen Óptica/métodos , Paclitaxel/administración & dosificación , Selección de Paciente , Reproducibilidad de los Resultados , Nanomedicina Teranóstica/métodos , Distribución Tisular , Microambiente Tumoral/efectos de los fármacosRESUMEN
In recent years, cancer immunotherapy has evolved as an exciting novel strategy for researchers and clinicians worldwide. Immunotherapeutic agents such as immune checkpoint blockers have changed the standard-of-care treatment provided for many tumors. Unfortunately, only a small proportion of patients respond effectively to these checkpoint inhibitors. Moreover, the immunosuppressive pathways for cancer are probably too complicated to achieve optimal outcome with immune checkpoint inhibitors alone. Combining current therapeutic options and immunotherapy-based approaches is being explored as an effective strategy to treat cancer. The use of nanotechnology-based platforms for delivery of immunotherapeutic agents or combination therapy could offer a major advantage over conventional anticancer treatment options. This review highlights the potential role of different nanotechnology-based strategies in improving the efficacy of immune checkpoint blockade therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias/tratamiento farmacológico , Nanomedicina Teranóstica/métodos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Liposomas , Imagen Molecular/métodos , Sondas Moleculares/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias/diagnóstico por imagen , Neoplasias/inmunología , Nanomedicina Teranóstica/tendencias , Resultado del TratamientoRESUMEN
PURPOSE: Hyaluronan (HA) based biomaterials are widely used as tissue scaffolds, drug formulations, as well as targeting ligands and imaging probes for diagnosis and drug delivery. However, because of the presence of abundant endogenous HA presented in various tissues in vivo, the pharmacokinetic behavior and biodistribution patterns of exogenously administered HAs have not been well characterized. METHODS: The HA backbone was modified with Diethylenetriamine (DTPA) to enable the chelation of gadolinium (Gd) and aluminum (Al) ions. Series of PET and MR imaging were taken after the injection of HA-DTPA-Gd and HA-DTPA-Al18F while using18F-FDG and Magnevist(DTPA-Gd) as controls. The Tomographic images were analyzed and quantified to reveal the distribution and locations of HA in tumor-bearing mice. RESULTS: The labeled HAs had good stability in plasma. They retained binding affinity towards CD44s on tumor cell surface. The injected HAs distributed widely in various organs, but were found to be cleared quickly except inside tumor tissues where the signals were higher and persisted longer. CONCLUSION: Medical imaging tools, including MR and PET, can be highly valuable for examining biomaterial distribution non-invasively. The HA tumor accumulation properties may be explored for the development of active targeting drug carriers and molecular probes.
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Materiales Biocompatibles/farmacocinética , Portadores de Fármacos/farmacocinética , Ácido Hialurónico/farmacocinética , Sondas Moleculares/farmacocinética , Células A549 , Animales , Materiales Biocompatibles/administración & dosificación , Medios de Contraste , Portadores de Fármacos/administración & dosificación , Humanos , Ácido Hialurónico/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Ratones , Sondas Moleculares/administración & dosificación , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Tomografía de Emisión de Positrones , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Radionuclide molecular imaging of cancer-specific targets is a promising method to identify patients for targeted antibody therapy. Radiolabeled full-length antibodies however suffer from slow clearance, resulting in high background radiation. To overcome this problem, a pretargeting system based on complementary peptide nucleic acid (PNA) probes has been investigated. The pretargeting relies on sequential injections of primary, PNA-tagged antibody and secondary, radiolabeled PNA probe, which are separated in time, to allow for clearance of non-bound primary agent. We now suggest to include a clearing agent (CA), designed for removal of primary tumor-targeting agent from the blood. The CA is based on the antibody cetuximab, which was conjugated to PNA and lactosaminated by reductive amination to improve hepatic clearance. The CA was evaluated in combination with PNA-labelled trastuzumab, T-ZHP1, for radionuclide HER2 pretargeting. Biodistribution studies in normal mice demonstrated that the CA cleared ca. 7 times more rapidly from blood than unmodified cetuximab. Injection of the CA 6 h post injection of the radiolabeled primary agent [131I]I-T-ZHP1 gave a moderate reduction of the radioactivity concentration in the blood after 1 h from 8.5 ± 1.8 to 6.0 ± 0.4%ID/g. These proof-of-principle results could guide future development of a more efficient CA.
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Anticuerpos Antineoplásicos/administración & dosificación , Anticuerpos Antineoplásicos/química , Inmunoconjugados/administración & dosificación , Inmunoconjugados/química , Ácidos Nucleicos de Péptidos/administración & dosificación , Ácidos Nucleicos de Péptidos/química , Radioinmunoterapia/métodos , Animales , Anticuerpos Antineoplásicos/metabolismo , Línea Celular Tumoral , Cetuximab/administración & dosificación , Cetuximab/sangre , Cetuximab/química , Femenino , Humanos , Inmunoconjugados/farmacocinética , Ratones , Sondas Moleculares/administración & dosificación , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Terapia Molecular Dirigida/métodos , Ácidos Nucleicos de Péptidos/farmacocinética , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/inmunología , Distribución Tisular , Trastuzumab/administración & dosificación , Trastuzumab/sangre , Trastuzumab/químicaRESUMEN
Aptamers are short single-stranded oligonucleotides that have attracted considerable attention due to their favorable biological characteristics. Aptamers can specifically target and bind to proteins or tumor cells, achieving tumor diagnosis and therapy in vitro and in vivo. Following an introduction of methodologies of producing aptamers and the recent advances of aptamers being applied to clinical samples or xenograft tumors, tumor diagnosis using aptamers will be reviewed, including fluorescence imaging, radionuclide-based imaging, MRI, histochemical imaging, and multimodality imaging. Preclinical applications in tumor therapy in vivo will also be discussed, covering different kinds of treatment mechanisms, including aptamer therapeutics, chemotherapy, gene therapy, immunotherapy, and combination therapy. Safety and efficacy of tumor-targeting therapeutics via aptamers, as well as the current challenges and future perspectives about aptamers' clinical applications, will be summarized.
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Antineoplásicos/administración & dosificación , Aptámeros de Nucleótidos/administración & dosificación , Portadores de Fármacos/síntesis química , Sondas Moleculares/administración & dosificación , Neoplasias/terapia , Animales , Antineoplásicos/síntesis química , Aptámeros de Nucleótidos/síntesis química , Aptámeros de Nucleótidos/farmacología , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Ensayos Clínicos Fase I como Asunto , Terapia Combinada/métodos , Terapia Combinada/tendencias , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Terapia Genética/métodos , Terapia Genética/tendencias , Humanos , Inmunoterapia/métodos , Inmunoterapia/tendencias , Imagen Molecular/métodos , Imagen Molecular/tendencias , Sondas Moleculares/síntesis química , Sondas Moleculares/farmacología , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patología , Técnica SELEX de Producción de Aptámeros/tendenciasRESUMEN
Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer cells and therefore is an attractive target for prostate cancer diagnosis and radionuclide therapy. Recently, published results from clinical studies using a new PSMA-targeting PET imaging agent, [68Ga]Ga-PSMA-093 ([68Ga]Ga-HBED-CC-O-carboxymethyl-Tyr-CO-NH-Glu), support the development of this agent for the diagnosis of prostate cancer. In this study, the HBED-CC chelating group in PSMA-093 was replaced by stereoselective (R)- or (S)-DOTAGA. This chelating group serves not only for chelating 68Ga but is also amendable for complexing other radioactive metals for radionuclide therapy. The corresponding optically pure (R)- and (S)-[68Ga/177Lu]-DOTAGA derivatives, (R)-[68Ga/177Lu]-13 and (S)-[68Ga/177Lu]-13, were successfully prepared. Comparison of radiolabeling, binding affinity, cell uptake, and biodistribution between the two isomers was performed. Radiolabeling of (R)-[177Lu]Lu-13 and (S)-[177Lu]Lu-13 at 50 °C suggested that rates of complex formation were time-dependent and the formation of (S)-[177Lu]Lu-13 was distinctly faster. The rates of complex formation for the corresponding 68Ga agents were comparable between structural isomers. The natGa and natLu equivalents showed high binding PSMA affinity (IC50 = 24-111 nM), comparable to that of the parent agent, [natGa]Ga-PSMA-093 (IC50 = 34.0 nM). Results of cell uptake and biodistribution studies in PSMA-expressing PC3-PIP tumor-bearing mice appeared to show no difference between the labeled (R)- and (S)-isomers. This is the first time that a pair of [68Ga/177Lu]-(R)- and (S)-DOTAGA isomers of PSMA agents were evaluated. Results of biological studies between the isomers showed no noticeable difference; however, the distinctions on the rate of Lu complex formation should be considered in the development of new 177Lu-DOTAGA-based radionuclide therapy agents in the future.
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Antígenos de Superficie/metabolismo , Glutamato Carboxipeptidasa II/metabolismo , Sondas Moleculares/farmacocinética , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Radiofármacos/farmacocinética , Animales , Línea Celular Tumoral , Quelantes/administración & dosificación , Quelantes/síntesis química , Quelantes/farmacocinética , Radioisótopos de Galio , Humanos , Concentración 50 Inhibidora , Lutecio , Masculino , Ratones , Imagen Molecular/métodos , Sondas Moleculares/administración & dosificación , Sondas Moleculares/síntesis química , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Radioisótopos , Radiofármacos/administración & dosificación , Radiofármacos/síntesis química , Estereoisomerismo , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The hypoxic microenvironment in solid tumors severely limits the efficacy of photodynamic therapy (PDT). Therefore, the development of nanocarriers co-loaded with photosensitizers and oxygen, together with imaging guidance ability, is of great significance in cancer therapy. However, previously reported synthetic methods for these multi-functional probes are complicated, and the raw materials used are toxic. Methods: Herein, the human endogenous protein, hemoglobin (Hb), was used for the simultaneous biomimetic synthesis of Gd-based nanostructures and co-loading of Chlorine e6 (Ce6) and oxygen for alleviating the hypoxic environment of tumors and accomplishing magnetic resonance imaging (MRI)-guided enhanced PDT. The Gd@HbCe6-PEG nanoprobes were synthesized via a green and protein biomimetic approach. The physicochemical properties, including relaxivity, oxygen-carrying/release capability, and PDT efficacy of Gd@HbCe6-PEG, were measured in vitro and in vivo on tumor-bearing mice after intravenous injection. Morphologic and functional MRI were carried out to evaluate the efficacy of PDT. Results: The results demonstrated the successful synthesis of compact Gd@HbCe6-PEG nanostructures with desired multi-functionalities. Following treatment with the nanoparticles, the embedded MR moiety was effective in lighting tumor lesions and guiding therapy. The oxygen-carrying capability of Hb after biomimetic synthesis was confirmed by spectroscopic analysis and oxygen detector in vitro. Further, tumor oxygenation for alleviating tumor hypoxia in vivo after intravenous injection of Gd@HbCe6-PEG was verified by photoacoustic imaging and immunofluorescence staining. The potent treatment efficacy of PDT on early-stage was observed by the morphologic and functional MR imaging. Importantly, rapid renal clearance of the particles was observed after treatment. Conclusion: In this study, by using a human endogenous protein, we demonstrated the biomimetic synthesis of multi-functional nanoprobes for simultaneous tumor oxygenation and imaging-guided enhanced PDT. The therapeutic efficacy could be quantitatively confirmed at 6 h post PDT with diffusion-weighted imaging (DWI).
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Antineoplásicos/administración & dosificación , Nanopartículas del Metal/administración & dosificación , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Nanomedicina Teranóstica/métodos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Materiales Biomiméticos/administración & dosificación , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/farmacocinética , Línea Celular Tumoral/trasplante , Clorofilidas , Imagen de Difusión por Resonancia Magnética , Modelos Animales de Enfermedad , Femenino , Gadolinio/administración & dosificación , Gadolinio/química , Tecnología Química Verde , Hemoglobinas/administración & dosificación , Hemoglobinas/química , Humanos , Inyecciones Intravenosas , Nanopartículas del Metal/química , Ratones , Sondas Moleculares/administración & dosificación , Sondas Moleculares/síntesis química , Sondas Moleculares/farmacocinética , Neoplasias/diagnóstico por imagen , Oxígeno/administración & dosificación , Oxígeno/química , Técnicas Fotoacústicas , Porfirinas/administración & dosificación , Porfirinas/química , Hipoxia Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
PURPOSE: To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC. EXPERIMENTAL DESIGN: Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101. RESULTS: In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS P = 0.028, DFS P = 0.047). CPA increased the prognostic accuracy of a multivariable logistic regression model comprised of previously established PDAC risk factors [AUC CPA (-) = 0.76, AUC CPA (+) = 0.82]. In multiple murine orthotopic PDAC models, FOLFIRINOX therapy reduced tumor weight (P < 0.05) and increased tumor fibrosis by collagen staining (P < 0.05). CM-101 MR signal was significantly increased in fibrotic tumor regions. CM-101 signal retention was also increased in the more fibrotic FOLFIRINOX-treated tumors compared with untreated controls (P = 0.027), consistent with selective probe binding to collagen. No treatment-related differences were observed with Gd-DOTA imaging. CONCLUSIONS: In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.
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Carcinoma Ductal Pancreático/terapia , Quimioradioterapia Adyuvante , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/epidemiología , Páncreas/patología , Neoplasias Pancreáticas/terapia , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Colágeno/análisis , Colágeno/metabolismo , Supervivencia sin Enfermedad , Femenino , Fibrosis , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Compuestos Heterocíclicos/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Persona de Mediana Edad , Imagen Molecular/métodos , Sondas Moleculares/administración & dosificación , Recurrencia Local de Neoplasia/prevención & control , Compuestos Organometálicos/administración & dosificación , Oxaliplatino/administración & dosificación , Páncreas/diagnóstico por imagen , Páncreas/cirugía , Pancreatectomía , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Targeted therapies for cancer have accelerated the need for functional imaging strategies that inform therapeutic efficacy. This study assesses the potential of functional genetic screening to integrate therapeutic target identification with imaging probe selection through a proof-of-principle characterization of a therapy-probe pair using dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI). EXPERIMENTAL DESIGN: CRISPR-negative selection screens from a public dataset were used to identify the relative dependence of 625 cancer cell lines on 18,333 genes. Follow-up screening was performed in hepatocellular carcinoma with a focused CRISPR library targeting imaging-related genes. Hyperpolarized [1-13C]-pyruvate was injected before and after lactate dehydrogenase inhibitor (LDHi) administration in male Wistar rats with autochthonous hepatocellular carcinoma. MRSI evaluated intratumoral pyruvate metabolism, while T2-weighted segmentations quantified tumor growth. RESULTS: Genetic screening data identified differential metabolic vulnerabilities in 17 unique cancer types that could be imaged with existing probes. Among these, hepatocellular carcinoma required lactate dehydrogenase (LDH) for growth more than the 29 other cancer types in this database. LDH inhibition led to a decrease in lactate generation (P < 0.001) and precipitated dose-dependent growth inhibition (P < 0.01 overall, P < 0.05 for dose dependence). Intratumoral alanine production after inhibition predicted the degree of growth reduction (P < 0.001). CONCLUSIONS: These findings demonstrate that DNP-MRSI of LDH activity using hyperpolarized [1-13C]-pyruvate is a theranostic strategy for hepatocellular carcinoma, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening informs imaging probe selection to quantify therapeutic efficacy on a cancer-by-cancer basis.
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Espectroscopía de Resonancia Magnética con Carbono-13/métodos , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas Experimentales/diagnóstico , Neoplasias Hepáticas/diagnóstico , Imagen Molecular/métodos , Animales , Sistemas CRISPR-Cas/genética , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Conjuntos de Datos como Asunto , Dietilnitrosamina/administración & dosificación , Dietilnitrosamina/toxicidad , Detección Precoz del Cáncer/métodos , Humanos , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Ácido Láctico/metabolismo , Hígado/diagnóstico por imagen , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/genética , Neoplasias Hepáticas Experimentales/patología , Masculino , Sondas Moleculares/administración & dosificación , Sondas Moleculares/farmacocinética , Medicina de Precisión/métodos , Prueba de Estudio Conceptual , Ácido Pirúvico/metabolismo , RatasRESUMEN
Tumor metastases, that is, the development of secondary tumors in organs distant from the primary tumor, and their treatment remain a serious problem in cancer therapy. The unique challenges for tracking and treating tumor metastases lie in the small size, high heterogeneity, and wide dispersion to distant organs of metastases. Recently, nanomedicines, with the capacity to precisely deliver therapeutic agents to both primary and secondary tumors, have demonstrated many potential benefits for metastatic cancer theranostics. Given the remarkable progression in emerging nanotherapeutics for antimetastatic treatment, it is timely to summarize the latest advances in this field. This review highlights the rationale, advantages, and challenges for integrating biomedical nanotechnology with cancer biology to develop antimetastatic nanotherapeutics.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Nanopartículas/administración & dosificación , Metástasis de la Neoplasia/tratamiento farmacológico , Nanomedicina Teranóstica/métodos , Microambiente Tumoral/efectos de los fármacos , Humanos , Imagen Molecular/métodos , Sondas Moleculares/administración & dosificación , Metástasis de la Neoplasia/diagnóstico , Células Neoplásicas Circulantes/efectos de los fármacosRESUMEN
Glutathione (GSH) is often upregulated in cancer, where it serves to mitigate oxidative stress. γ-glutamyl-transferase (GGT) is a key enzyme in GSH homeostasis, and compared to normal brain its expression is elevated in tumors, including in primary glioblastoma. GGT is therefore an attractive imaging target for detection of glioblastoma. The goal of our study was to assess the value of hyperpolarized (HP) γ-glutamyl-[1-13C]glycine for non-invasive imaging of glioblastoma. Nude rats bearing orthotopic U87 glioblastoma and healthy controls were investigated. Imaging was performed by injecting HP γ-glutamyl-[1-13C]glycine and acquiring dynamic 13C data on a preclinical 3T MR scanner. The signal-to-noise (SNR) ratios of γ-glutamyl-[1-13C]glycine and its product [1-13C]glycine were evaluated. Comparison of control and tumor-bearing rats showed no difference in γ-glutamyl-[1-13C]glycine SNR, pointing to similar delivery to tumor and normal brain. In contrast, [1-13C]glycine SNR was significantly higher in tumor-bearing rats compared to controls, and in tumor regions compared to normal-appearing brain. Importantly, higher [1-13C]glycine was associated with higher GGT expression and higher GSH levels in tumor tissue compared to normal brain. Collectively, this study demonstrates, to our knowledge for the first time, the feasibility of using HP γ-glutamyl-[1-13C]glycine to monitor GGT expression in the brain and thus to detect glioblastoma.
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Encéfalo/diagnóstico por imagen , Glioblastoma/diagnóstico , Imagen por Resonancia Magnética/métodos , Imagen Molecular/métodos , gamma-Glutamiltransferasa/metabolismo , Animales , Encéfalo/patología , Isótopos de Carbono/administración & dosificación , Isótopos de Carbono/química , Línea Celular Tumoral , Dipéptidos/administración & dosificación , Dipéptidos/química , Estudios de Factibilidad , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Humanos , Masculino , Sondas Moleculares/administración & dosificación , Sondas Moleculares/química , Ratas , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Currently, there are no non-invasive tools to accurately diagnose wound and surgical site infections before they become systemic or cause significant anatomical damage. Fluorescence and photoacoustic imaging are cost-effective imaging modalities that can be used to noninvasively diagnose bacterial infections when paired with a molecularly targeted infection imaging agent. Here, we develop a fluorescent derivative of maltotriose (Cy7-1-maltotriose), which is shown to be taken up in a variety of gram-positive and gram-negative bacterial strains in vitro. In vivo fluorescence and photoacoustic imaging studies highlight the ability of this probe to detect infection, assess infection burden, and visualize the effectiveness of antibiotic treatment in E. coli-induced myositis and a clinically relevant S. aureus wound infection murine model. In addition, we show that maltotriose is an ideal scaffold for infection imaging agents encompassing better pharmacokinetic properties and in vivo stability than other maltodextrins (e.g. maltohexose).
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Colorantes Fluorescentes/administración & dosificación , Imagen Molecular/métodos , Miositis/diagnóstico por imagen , Infección de la Herida Quirúrgica/diagnóstico por imagen , Trisacáridos/administración & dosificación , Animales , Carbocianinas/administración & dosificación , Carbocianinas/química , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Escherichia coli/aislamiento & purificación , Escherichia coli/metabolismo , Femenino , Colorantes Fluorescentes/química , Colorantes Fluorescentes/metabolismo , Humanos , Inyecciones Intravenosas , Mediciones Luminiscentes/métodos , Ratones , Microscopía Fluorescente/métodos , Sondas Moleculares/administración & dosificación , Sondas Moleculares/química , Sondas Moleculares/metabolismo , Miositis/microbiología , Técnicas Fotoacústicas/métodos , Ratas , Staphylococcus aureus/aislamiento & purificación , Staphylococcus aureus/metabolismo , Infección de la Herida Quirúrgica/microbiología , Trisacáridos/química , Trisacáridos/metabolismoRESUMEN
Novel red Zn(ii) complex-based fluorescent probes featuring cryptolepine-curcumin derivatives, namely, [Zn(BQ)Cl2] (BQ-Zn) and [Zn(BQ)(Cur)]Cl (BQCur-Zn), were developed for the simple and fluorescent label-free detection of apoptosis, an important biological process. The probes could synergistically promote mitochondrion-mediated apoptosis and enhance tumor therapeutic effects in vitro and vivo.
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Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Curcumina/administración & dosificación , Colorantes Fluorescentes/administración & dosificación , Alcaloides Indólicos/administración & dosificación , Sondas Moleculares/administración & dosificación , Quinolinas/administración & dosificación , Zinc/administración & dosificación , Animales , Línea Celular Tumoral , Humanos , Ratones , Neoplasias/tratamiento farmacológico , FotoquimioterapiaRESUMEN
Herein we report a pair of redox-responsive manganese complexes Mn(iii)/(ii)-N,N'-bis(2-hydroxy-4-trifluoromethylbenzyl)ethylenediamine-N,N'-diacetate (HTFBED, L1), which are water soluble and biologically interconvertible, as reversible redox-responsive probes in 1H/19F MRI for detecting and imaging biological redox species, offering a means to access valuable redox information associated with various diseases.
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Complejos de Coordinación , Ácido Edético , Manganeso , Sondas Moleculares , Acetilcisteína/análogos & derivados , Acetilcisteína/farmacología , Antioxidantes/farmacología , Ácido Ascórbico/farmacología , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Complejos de Coordinación/administración & dosificación , Complejos de Coordinación/química , Ácido Edético/administración & dosificación , Ácido Edético/análogos & derivados , Ácido Edético/química , Células Hep G2 , Humanos , Imagen por Resonancia Magnética , Manganeso/administración & dosificación , Manganeso/química , Sondas Moleculares/administración & dosificación , Sondas Moleculares/química , Oxidación-Reducción , Piocianina/farmacologíaRESUMEN
PURPOSE: Probe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH. METHODS: Rosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate. RESULTS: For rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive. CONCLUSIONS: These data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.
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Técnicas de Cultivo de Célula , Hepatocitos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Sondas Moleculares/química , Transporte Biológico , Células Cultivadas , Digoxina/administración & dosificación , Digoxina/química , Digoxina/metabolismo , Estolato de Eritromicina/administración & dosificación , Estolato de Eritromicina/farmacología , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Humanos , Metformina/administración & dosificación , Metformina/química , Metformina/metabolismo , Sondas Moleculares/administración & dosificación , Sondas Moleculares/metabolismo , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/metabolismoRESUMEN
Carbonic anhydrase IX (CAIX) is a cancer-associated molecular target for several classes of therapeutics. CAIX is overexpressed in a large fraction of renal cell carcinomas (RCC). Radionuclide molecular imaging of CAIX-expression might offer a non-invasive methodology for stratification of patients with disseminated RCC for CAIX-targeting therapeutics. Radiolabeled monoclonal antibodies and their fragments are actively investigated for imaging of CAIX expression. Promising alternatives are small non-immunoglobulin scaffold proteins, such as affibody molecules. A CAIX-targeting affibody ZCAIX:2 was re-designed with the aim to decrease off-target interactions and increase imaging contrast. The new tracer, DOTA-HE3-ZCAIX:2, was labeled with 111In and characterized in vitro. Tumor-targeting properties of [111In]In-DOTA-HE3-ZCAIX:2 were compared head-to-head with properties of the parental variant, [99mTc]Tc(CO)3-HE3-ZCAIX:2, and the most promising antibody fragment-based tracer, [111In]In-DTPA-G250(Fab')2, in the same batch of nude mice bearing CAIX-expressing RCC xenografts. Compared to the 99mTc-labeled parental variant, [111In]In-DOTA-HE3-ZCAIX:2 provides significantly higher tumor-to-lung, tumor-to-bone and tumor-to-liver ratios, which is essential for imaging of CAIX expression in the major metastatic sites of RCC. [111In]In-DOTA-HE3-ZCAIX:2 offers significantly higher tumor-to-organ ratios compared with [111In]In-G250(Fab')2. In conclusion, [111In]In-DOTA-HE3-ZCAIX:2 can be considered as a highly promising tracer for imaging of CAIX expression in RCC metastases based on our results and literature data.