RESUMEN
Theranostic nanoparticles hold the potential to greatly improve cancer management by providing personalized medicine. Although many theranostic nanoconstructs have been successful in preclinical studies, clinical translation is still hampered by their limited targeting capability and lack of successful therapeutic efficacy. We report the use of novel ultrasmall porous silica nanoparticles (UPSN) with enhanced in vivo pharmacokinetics such as high target tissue accumulation (12% ID/g in the tumor) and evasion from the reticuloendothelial system (RES) organs. Herein, UPSN is conjugated with the isotopic pair 90/86Y, enabling both noninvasive imaging as well as internal radiotherapy. In vivo PET imaging demonstrates prolonged blood circulation and excellent tumor contrast with 86Y-DOTA-UPSN. Tumor-to-muscle and tumor-to-liver uptake values were significantly high (12.4 ± 1.7 and 1.5 ± 0.5, respectively), unprecedented for inorganic nanomaterials. 90Y-DOTA-UPSN significantly inhibits tumor growth and increases overall survival, indicating the promise of UPSN for future clinical translation as a cancer theranostic agent.
Asunto(s)
Nanopartículas , Neoplasias , Línea Celular Tumoral , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Porosidad , Medicina de Precisión , Dióxido de SilicioRESUMEN
Pancreatic cancer is highly aggressive, with a median survival time of less than 6 months and a 5-year overall survival rate of around 7%. The poor prognosis of PaCa is largely due to its advanced stage at diagnosis and the lack of efficient therapeutic options. Thus, the development of an efficient, multifunctional PaCa theranostic system is urgently needed. Overexpression of tissue factor (TF) has been associated with increased tumor growth, angiogenesis, and metastasis in many malignancies, including pancreatic cancer. Herein, we propose the use of a TF-targeted monoclonal antibody (ALT836) conjugated with the pair 86/90Y as a theranostic agent against pancreatic cancer. For methods, serial PET imaging with 86Y-DTPA-ALT836 was conducted to map the biodistribution the tracer in BXPC-3 tumor-bearing mice. 90Y-DTPA-ALT836 was employed as a therapeutic agent that also allowed tumor burden monitoring through Cherenkov luminescence imaging. The results were that the uptake of 86Y-DTPA-ALT836 in BXPC-3 xenograft tumors was high and increased over time up to 48 h postinjection (p.i.), corroborated through ex vivo biodistribution studies and further confirmed by Cherenkov luminescence Imaging. In therapeutic studies, 90Y-DTPA-ALT836 was found to slow tumor growth relative to the control groups and had significantly smaller (p < 0.05) tumor volumes 1 day p.i. Histological analysis of ex vivo tissues revealed significant damage to the treated tumors. The conclusion is that the use of the 86/90Y theranostic pair allows PET imaging with excellent tumor-to-background contrast and treatment of TF-expressing pancreatic tumors with promising therapeutic outcomes.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Tromboplastina/antagonistas & inhibidores , Radioisótopos de Itrio/farmacocinética , Animales , Anticuerpos Monoclonales/farmacocinética , Línea Celular Tumoral , Femenino , Ratones , Neoplasias Pancreáticas/patología , Tomografía de Emisión de Positrones , Distribución TisularRESUMEN
Effective therapy for protecting dying neurons against cerebral ischemia-reperfusion injury (IRI) represents a substantial challenge in the treatment of ischemic strokes. Oxidative stress coupled with excessive inflammation is the main culprit for brain IRI that results in neuronal damage and disability. Specifically, complement component 5a (C5a) exacerbates the vicious cycle between oxidative stress and inflammatory responses. Herein, we propose that a framework nucleic acid (FNA) conjugated with anti-C5a aptamers (aC5a) can selectively reduce C5a-mediated neurotoxicity and effectively alleviate oxidative stress in the brain. Intrathecal injection of the aC5a-conjugated FNA (aC5a-FNA) was applied for the treatment of rats with ischemic strokes. Positron emission tomography (PET) imaging was performed to investigate the accumulation of aC5a-FNA in the penumbra and its therapeutic efficacy. Results demonstrated that aC5a-FNA could rapidly penetrate different brain regions after brain IRI. Furthermore, aC5a-FNA effectively protected neurons from brain IRI, as verified by serum tests, tissue staining, biomarker detection, and functional assessment. The protective effect of aC5a-FNA against cerebral IRI in living animals may pave the way for the translation of FNA from bench to bedside and broaden the horizon of FNA in the field of biomedicine.
Asunto(s)
Aptámeros de Nucleótidos/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Complemento C5a/antagonistas & inhibidores , Ácidos Nucleicos/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Animales , Aptámeros de Nucleótidos/administración & dosificación , Isquemia Encefálica/inmunología , Isquemia Encefálica/patología , Complemento C5a/inmunología , Inyecciones Espinales , Ácidos Nucleicos/administración & dosificación , Ratas Sprague-Dawley , Daño por Reperfusión/inmunología , Daño por Reperfusión/patologíaRESUMEN
Acute kidney injury (AKI) is frequently associated with oxidative stress and causes high mortality annually in clinics. Nanotechnology-mediated antioxidative therapy is emerging as a novel strategy for the treatment of AKI. Herein, a novel biomedical use of the endogenous biopolymer melanin as a theranostic natural antioxidant defense nanoplatform for AKI is reported. In this study, ultrasmall Mn2+-chelated melanin (MMP) nanoparticles are easily prepared via a simple coordination and self-assembly strategy, and further incorporated with polyethylene glycol (MMPP). In vitro experiments reveal the ability of MMPP nanoparticles to scavenge multiple toxic reactive oxygen species (ROS) and suppress ROS-induced oxidative stress. Additionally, in vivo results from a murine AKI model demonstrate preferential renal uptake of MMPP nanoparticles and a subsequent robust antioxidative response with negligible side effects according to positron emission tomography/magnetic resonance (PET/MR) bimodal imaging and treatment assessment. These results indicate that the effectiveness of MMPP nanoparticles for treating AKI suggests the potential efficacy of melanin as a natural theranostic antioxidant nanoplatform for AKI, as well as other ROS-related diseases.
RESUMEN
Chronic inflammatory diseases are often progressive, resulting not only in physical damage to patients but also social and economic burdens, making early diagnosis of them critical. Nuclear medicine techniques can enhance the detection of inflammation by providing functional as well as anatomical information when combined with other modalities such as magnetic resonance imaging, computed tomography or ultrasonography. Although small molecules and peptides were mainly used for the treatment and imaging of chronic inflammatory diseases in the past, antibodies and their fragments have also been emerging for chronic inflammatory diseases as they show high specificity to their targets and can have various biological half-lives depending on how they are engineered. In addition, imaging with antibodies or their fragments can visualize the in vivo biodistribution of the probes or help monitor therapeutic responses, thereby providing physicians with a greater understanding of drug behavior in vivo and another means of monitoring their patients. In this review, we introduce various targets and radiolabeled antibody-based probes for the molecular imaging of chronic inflammatory diseases in preclinical and clinical studies. Targets can be classified into three different categories: 1)â cell-adhesion molecules, 2)â surface markers on immune cells, and 3)â cytokines or enzymes. The limitations and future directions of using radiolabeled antibodies for imaging inflammatory diseases are also discussed.
Asunto(s)
Anticuerpos/inmunología , Enfermedades Autoinmunes/diagnóstico por imagen , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Animales , Anticuerpos/química , Antígenos de Superficie/inmunología , Antígenos de Superficie/metabolismo , Aterosclerosis/diagnóstico por imagen , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , HumanosRESUMEN
Immune checkpoint expression is highly dynamic, and combination treatments including radiotherapy can particularly modulate this expression. PET imaging using 89Zr-Df-atezolizumab can provide insight into the levels of PD-L1 variation following radiotherapy treatments. In vitro screening was used to monitor PD-L1 expression by lung cancer cells following radiotherapy. Mice bearing PD-L1+ (H460) or PD-L1- (A549) tumors were subjected to various external beam radiotherapy regimens and then imaged using 89Zr-Df-atezolizumab PET. ROI analysis and ex vivo biodistribution studies were employed to quantify tracer accumulations. H460 cells were found to have PD-L1 expression at baseline, and this expression increased following daily radiotherapy of 5 fractions of 2 Gy. PD-L1 expression could not be induced on A549 cells, regardless of radiotherapy regimen. The increase in PD-L1 expression in H460 tumors following fractionated radiotherapy could be imaged in vivo using 89Zr-Df-atezolizumab, with statistically significant higher tracer accumulation noted in fractionated H460 tumors over that in all other H460 or A549 groups after 72 h postinjection of the tracer. Significant accumulation of the tracer was also noted in other PD-L1+ organs, including the spleen and lymph nodes. Ex vivo staining of tumor tissues verified that tumor cells as well as tumor-infiltrating immune cells were responsible for increased PD-L1 expression after radiotherapy in tumor tissues. Overall, PD-L1 expression can be modulated with radiotherapy interventions, and 89Zr-Df-atezolizumab is able to noninvasively monitor these changes in preclinical models.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Antígeno B7-H1/metabolismo , Radiofármacos/química , Regulación hacia Arriba , Circonio/química , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/inmunología , Antígeno B7-H1/inmunología , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapiaRESUMEN
As one of the most biocompatible and well-tolerated inorganic nanomaterials, silica-based nanoparticles (SiNPs) have received extensive attention over the last several decades. Recently, positron emission tomography (PET) imaging of radiolabeled SiNPs has provided a highly sensitive, noninvasive, and quantitative readout of the organ/tissue distribution, pharmacokinetics, and tumor targeting efficiency in vivo, which can greatly expedite the clinical translation of these promising NPs. Encouraged by the successful PET imaging of patients with metastatic melanoma using 124I-labeled ultrasmall SiNPs (known as Cornell dots or C dots) and their approval as an Investigational New Drug (IND) by the United States Food and Drug Administration, different radioisotopes (64Cu, 89Zr, 18F, 68Ga, 124I, etc.) have been reported to radiolabel a wide variety of SiNPs-based nanostructures, including dense silica (dSiO2), mesoporous silica (MSN), biodegradable mesoporous silica (bMSN), and hollow mesoporous silica nanoparticles (HMSN). With in-depth knowledge of coordination chemistry, abundant silanol groups (-Si-O-) on the silica surface or inside mesoporous channels not only can be directly used for chelator-free radiolabeling but also can be readily modified with the right chelators for chelator-based labeling. However, integrating these labeling strategies for constructing stably radiolabeled SiNPs with high efficiency has proven difficult because of the complexity of the involved key parameters, such as the choice of radioisotopes and chelators, nanostructures, and radiolabeling strategy. In this Account, we present an overview of recent progress in the development of radiolabeled SiNPs for cancer theranostics in the hope of speeding up their biomedical applications and potential translation into the clinic. We first introduce the basic principles and mechanisms for radiolabeling SiNPs via coordination chemistry, including general rules of selecting proper radioisotopes, engineering silica nanoplatforms (e.g., dSiO2, MSN, HMSN) accordingly, and chelation strategies for enhanced labeling efficiency and stability, on which our group has focused over the past decade. Generally, the medical applications guide the choice of specific SiNPs for radiolabeling by considering the inherent functionality of SiNPs. The radioisotopes can then be determined according to the amenability of the particular SiNPs for chelator-based or chelator-free radiolabeling to obtain high labeling stability in vivo, which is a prerequisite for PET to truly reflect the behavior of SiNPs since PET imaging detects the isotopes rather than nanoparticles. Next, we highlight several recent representative biomedical applications of radiolabeled SiNPs including molecular imaging to detect specific lesions, PET-guided drug delivery, SiNP-based theranostic cancer agents, and clinical studies. Finally, the challenges and prospects of radiolabeled SiNPs are briefly discussed toward clinical cancer research. We hope that this Account will clarify the recent progress on the radiolabeling of SiNPs for specific medical applications and generate broad interest in integrating nanotechnology and PET imaging. With several ongoing clinical trials, radiolabeled SiNPs offer great potential for future patient stratification and cancer management in clinical settings.
Asunto(s)
Nanopartículas/química , Neoplasias/diagnóstico por imagen , Dióxido de Silicio/química , Animales , Radioisótopos de Cobre , Radioisótopos de Flúor , Radioisótopos de Galio , Humanos , Radioisótopos de Yodo , Imagen Molecular , Neoplasias/tratamiento farmacológico , Tomografía de Emisión de Positrones , Radioisótopos , CirconioRESUMEN
The rapid ascension of immune checkpoint blockade treatments has placed an emphasis on the need for viable, robust, and noninvasive imaging methods for immune checkpoint proteins, which could be of diagnostic value. Immunoconjugate-based positron emission tomography (immuno-PET) allows for sensitive and quantitative imaging of target levels and has promising potential for the noninvasive evaluation of immune checkpoint proteins. However, the advancement of immuno-PET is currently limited by available imaging tools, which heavily rely on full-length IgGs with Fc-mediated effects and are heterogeneous mixtures upon random conjugation with chelators for imaging. Herein, we have developed a site-specific αPD-L1 Fab conjugate with the chelator 1,4,7-triazacyclononane- N, N', Nâ³-triacetic acid (NOTA), enabling radiolabeling for PET imaging, using the amber suppression-mediated genetic incorporation of unnatural amino acid (UAA), p-azidophenylalanine. This Fab conjugate is homogeneous and demonstrated tight binding toward the PD-L1 antigen in vitro. The radiolabeled version, 64Cu-NOTA-αPD-L1, has been employed in PET imaging to allow for effective visualization and mapping of the biodistribution of PD-L1 in two normal mouse models, including the capturing of different PD-L1 expression levels in the spleens of the different mouse types. Follow-up in vivo blocking studies and ex vivo fluorescent staining further validated specific tissue uptakes of the imaging agent. This approach illustrates the utility of UAA-based site-specific Fab conjugation as a general strategy for making sensitive PET imaging probes, which could facilitate the elucidation of the roles of a wide variety of immune checkpoint proteins in immunotherapy.
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Antígeno B7-H1/metabolismo , Sitios de Unión de Anticuerpos , Inmunoconjugados/farmacocinética , Tomografía de Emisión de Positrones/métodos , Trazadores Radiactivos , Animales , Azidas/química , Antígeno B7-H1/inmunología , Quelantes/química , Simulación por Computador , Radioisótopos de Cobre/química , Compuestos Heterocíclicos con 1 Anillo/química , Inmunoconjugados/inmunología , Fragmentos Fab de Inmunoglobulinas/genética , Fragmentos Fab de Inmunoglobulinas/inmunología , Inmunoterapia , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Mutación , Fenilalanina/análogos & derivados , Fenilalanina/química , Radiofármacos/farmacocinética , Receptor ErbB-2/inmunología , Receptor ErbB-2/metabolismo , Bazo/metabolismo , Distribución TisularRESUMEN
Positron emission tomography (PET) provides quantitative information inâ vivo with ultra-high sensitivity but is limited by its relatively low spatial resolution. Therefore, PET has been combined with other imaging modalities, and commercial systems such as PET/computed tomography (CT) and PET/magnetic resonance (MR) have become available. Inspired by the emerging field of nanomedicine, many PET-based multimodality nanoparticle imaging agents have been developed in recent years. This Minireview highlights recent progress in the design of PET-based multimodality imaging nanoprobes with an aim to overview the major advances and key challenges in this field and substantially improve our knowledge of this fertile research area.
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Colorantes Fluorescentes/química , Nanopartículas/química , Tomografía de Emisión de Positrones , Humanos , Imagen Multimodal , NanomedicinaRESUMEN
Melanoma represents the most aggressive form of skin cancer, and its incidence continues to rise worldwide. 18F-FDG PET imaging has transformed diagnostic nuclear medicine and has become an essential component in the management of melanoma, but still has its drawbacks. With the rapid growth in the field of nuclear medicine and molecular imaging, a variety of promising probes that enable early diagnosis and detection of melanoma have been developed. The substantial preclinical success of melanin- and peptide-based probes has recently resulted in the translation of several radiotracers to clinical settings for noninvasive imaging and treatment of melanoma in humans. In this review, we focus on the latest developments in radiolabeled molecular imaging probes for melanoma in preclinical and clinical settings, and discuss the challenges and opportunities for future development.
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Melanoma/diagnóstico por imagen , Radiofármacos/farmacocinética , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Humanos , Melanoma/patología , Melanoma/radioterapia , Metástasis de la Neoplasia , Unión Proteica , Radiofármacos/química , Radiofármacos/uso terapéuticoRESUMEN
Amino acid-based tracers have been extensively investigated for positron emission tomography (PET) imaging of brain tumors, and 11C-methionine (11C-MET) is one of the most extensively investigated. However, widespread clinical use of 11C-MET is challenging due to the short half-life of 11C and low radiolabeling yield. In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, Yang and colleagues report an 18F-labeled boron-derived methionine analog, 18F-B-MET, as a potential substitute for 11C-MET in PET imaging of glioma. The push-button synthesis, highly efficient radiolabeling, and good imaging performance in glioma models make this tracer a promising candidate for future clinical translation.
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Boro , Metionina , Neoplasias Encefálicas , Radioisótopos de Carbono , Glioma , Humanos , Tomografía de Emisión de PositronesRESUMEN
PURPOSE: Nivolumab is a human monoclonal antibody specific for programmed cell death-1 (PD-1), a negative regulator of T-cell activation and response. Acting as an immune checkpoint inhibitor, nivolumab binds to PD-1 expressed on the surface of many immune cells and prevents ligation by its natural ligands. Nivolumab is only effective in a subset of patients, and there is limited evidence supporting its use for diagnostic, monitoring, or stratification purposes. METHODS: 89Zr-Df-nivolumab was synthesized to map the biodistribution of PD-1-expressing tumor infiltrating T-cells in vivo using a humanized murine model of lung cancer. The tracer was developed by radiolabeling the antibody with the positron emitter zirconium-89 (89Zr). Imaging results were validated by ex vivo biodistribution studies, and PD-1 expression was validated by immunohistochemistry. Data obtained from PET imaging were used to determine human dosimetry estimations. RESULTS: The tracer showed elevated binding to stimulated PD-1 expressing T-cells in vitro and in vivo. PET imaging of 89Zr-Df-nivolumab allowed for clear delineation of subcutaneous tumors through targeting of localized activated T-cells expressing PD-1 in the tumors and salivary glands of humanized A549 tumor-bearing mice. In addition to tumor uptake, salivary and lacrimal gland infiltration of T-cells was noticeably visible and confirmed via histological analysis. CONCLUSIONS: These data support our claim that PD-1-targeted agents allow for tumor imaging in vivo, which may assist in the design and development of new immunotherapies. In the future, noninvasive imaging of immunotherapy biomarkers may assist in disease diagnostics, disease monitoring, and patient stratification.
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Anticuerpos Monoclonales/farmacocinética , Infiltración Leucémica/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Linfocitos T/metabolismo , Circonio/química , Animales , Anticuerpos Monoclonales/química , Células Cultivadas , Humanos , Infiltración Leucémica/patología , Pulmón/diagnóstico por imagen , Pulmón/patología , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Nivolumab , Receptor de Muerte Celular Programada 1/metabolismo , Radiofármacos/síntesis química , Distribución TisularRESUMEN
PURPOSE: Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy. METHODS: The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with 177Lu (t 1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: 177Lu only, TRC105 only, 177Lu-DTPA-IgG (a nonspecific antibody), 177Lu-DTPA-TRC105 low-dose, and 177Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of 177Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose 177Lu-DTPA-TRC105. RESULTS: Biodistribution studies indicated steady uptake of 177Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses. CONCLUSION: 177Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.
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Anticuerpos Monoclonales/uso terapéutico , Lutecio/química , Neoplasias Experimentales/radioterapia , Neovascularización Patológica/radioterapia , Radioinmunoterapia/métodos , Radioisótopos/química , Radiofármacos/uso terapéutico , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Línea Celular Tumoral , Endoglina/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/patología , Ácido Pentético/química , Radiofármacos/efectos adversos , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
CD30 has been considered a unique diagnostic and therapeutic target for CD30-positive lymphomas and some lung diseases. Additionally, CD30 has shown high expression in clinical lung cancer samples. In this study, 89Zr-radiolabeled brentuximab vedotin (BV) was developed for in vivo tracking of BV and imaging CD30 expression in lung cancer models via conjugation with desferrioxamine (Df). CD30 expression in three lung cancer cell lines (H460, H358, and A549) was quantified by Western blot. Flow cytometry and saturation binding assays were used to evaluate the binding capabilities of the tracer in vitro. After longitudinal positron emission tomography (PET) imaging and quantitative analysis were performed, ex vivo biodistribution and histological studies were used to verify PET results. Finally, dosimetric extrapolation of murine data to humans was performed. At the cellular level, CD30 was found to be expressed on H460 and A549 cells with the highest and lowest levels of expression, respectively. Both Df-BV and 89Zr-Df-BV displayed high binding affinity to H460 cells. PET images and their quantification verified that BV accumulated in H460 tumor models (9.93 ± 2.70% ID/g at 24 h after injection; n = 4) at the highest level, followed by H358 and A549 tumors (8.05 ± 2.43 and 5.00 ± 1.56% ID/g; n = 4). The nonspecific 89Zr-labeled IgG showed a low tumor uptake of 5.2 ± 1.0% ID/g for H460 models. Ex vivo biodistribution and fluorescence immunohistochemistry also corroborated these findings. Dosimetric results displayed safe dose estimations. Therefore, 89Zr-Df-BV provides a potential agent for evaluating CD30 expression noninvasively in lung cancer, and also for imaging of brentuximab vedotin for better understanding of its pharmacokinetics.
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Inmunoconjugados/metabolismo , Antígeno Ki-1/metabolismo , Neoplasias Pulmonares/metabolismo , Células A549 , Animales , Brentuximab Vedotina , Línea Celular Tumoral , Deferoxamina/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Linfoma/metabolismo , Ratones , Ratones Desnudos , Tomografía de Emisión de Positrones/métodos , Radioisótopos/metabolismo , Distribución Tisular/fisiología , Circonio/metabolismoRESUMEN
Angiogenesis is widely recognized as one of the hallmarks of cancer. Therefore, imaging and therapeutic agents targeted to angiogenic vessels may be widely applicable in many types of cancer. To this end, the theranostic isotope pair, 86Y and 90Y, were used to create a pair of agents for targeted imaging and therapy of neovasculature in murine breast cancer models using a chimeric anti-CD105 antibody, TRC105. Serial positron emission tomography imaging with 86Y-DTPA-TRC105 demonstrated high uptake in 4T1 tumors, peaking at 9.6 ± 0.3%ID/g, verified through ex vivo studies. Additionally, promising results were obtained in therapeutic studies with 90Y-DTPA-TRC105, wherein significantly ( p < 0.05) decreased tumor volumes were observed for the targeted treatment group over all control groups near the end of the study. Dosimetric extrapolation and tissue histological analysis corroborated trends found in vivo. Overall, this study demonstrated the potential of the pair 86/90Y for theranostics, enabling personalized treatments for cancer.
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Antineoplásicos/farmacología , Inmunoconjugados/farmacología , Neoplasias Mamarias Experimentales/radioterapia , Neovascularización Patológica/tratamiento farmacológico , Radioinmunoterapia/métodos , Nanomedicina Teranóstica/métodos , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral/trasplante , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inmunoconjugados/química , Inmunoconjugados/uso terapéutico , Neoplasias Mamarias Experimentales/diagnóstico por imagen , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Distribución Tisular , Resultado del Tratamiento , Radioisótopos de Itrio/química , Radioisótopos de Itrio/farmacología , Radioisótopos de Itrio/uso terapéuticoRESUMEN
Magnetic resonance imaging (MRI) is a highly valuable non-invasive imaging tool owing to its exquisite soft tissue contrast, high spatial resolution, lack of ionizing radiation, and wide clinical applicability. Contrast agents (CAs) can be used to further enhance the sensitivity of MRI to obtain information-rich images. Recently, extensive research efforts have been focused on the design and synthesis of high-performance inorganic nanoparticle-based CAs to improve the quality and specificity of MRI. Herein, the basic rules, including the choice of metal ions, effect of electron motion on water relaxation, and involved mechanisms, of CAs for MRI have been elucidated in detail. In particular, various design principles, including size control, surface modification (e.g. organic ligand, silica shell, and inorganic nanolayers), and shape regulation, to impact relaxation of water molecules have been discussed in detail. Comprehensive understanding of how these factors work can guide the engineering of future inorganic nanoparticles with high relaxivity. Finally, we have summarized the currently available strategies and their mechanism for obtaining high-performance CAs and discussed the challenges and future developments of nanoparticulate CAs for clinical translation in MRI.
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Medios de Contraste/química , Imagen por Resonancia Magnética , Nanopartículas/química , Medios de Contraste/síntesis químicaRESUMEN
Although various types of imaging agents have been developed for photoacoustic (PA) imaging, relatively few imaging agents exhibit high selectivity/sensitivity to the tumor microenvironment for on-demand PA imaging and therapy. Herein, molybdenum-based polyoxometalate (POM) clusters with the highest oxidation state of Mo(VI) (denoted as Ox-POM) were designed as novel agents for redox-activated PA imaging-guided photothermal therapy. Capable of escaping from recognition and capture by the liver and spleen, these renal clearable clusters with ultrasmall size (hydrodynamic size: 1.9 nm) can accumulate in the tumor, self-assemble into larger nanoclusters at low pH, and are reduced to NIR absorptive agents in the tumor microenvironment. Studies in 4T1 tumor-bearing mice indicated that these clusters could be employed for bioresponsive PA imaging-guided tumor ablation in vivo. Our finding is expected to establish a new physicochemical paradigm for the design of PA imaging agents based on clusters, bridging the conventional concepts of "molecule" and "nano" in the bioimaging field.
Asunto(s)
Complejos de Coordinación/química , Molibdeno/química , Nanopartículas/química , Técnicas Fotoacústicas/métodos , Fototerapia/métodos , Compuestos de Tungsteno/química , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Oxidación-Reducción , Nanomedicina Teranóstica , Distribución TisularRESUMEN
PURPOSE: Human epidermal growth factor receptor 2 (HER2) is over-expressed in over 30% of ovarian cancer cases, playing an essential role in tumorigenesis and metastasis. Non-invasive imaging of HER2 is of great interest for physicians as a mean to better detect and monitor the progression of ovarian cancer. In this study, HER2 was assessed as a biomarker for ovarian cancer imaging using 64Cu-labeled pertuzumab for immunoPET imaging. METHODS: HER2 expression and binding were examined in three ovarian cancer cell lines (SKOV3, OVCAR3, Caov3) using in vitro techniques, including western blot and saturation binding assays. PET imaging and biodistribution studies in subcutaneous models of ovarian cancer were performed for non-invasive in vivo evaluation of HER2 expression. Additionally, orthotopic models were employed to further validate the imaging capability of 64Cu-NOTA-pertuzumab. RESULTS: HER2 expression was highest in SKOV3 cells, while OVCAR3 and Caov3 displayed lower HER2 expression. 64Cu-NOTA-pertuzumab showed high specificity for HER2 (Ka = 3.1 ± 0.6 nM) in SKOV3. In subcutaneous tumors, PET imaging revealed tumor uptake of 41.8 ± 3.8, 10.5 ± 3.9, and 12.1 ± 2.3%ID/g at 48 h post-injection for SKOV3, OVCAR3, and Caov3, respectively (n = 3). In orthotopic models, PET imaging with 64Cu-NOTA-pertuzumab allowed for rapid and clear delineation of both primary and small peritoneal metastases in HER2-expressing ovarian cancer. CONCLUSIONS: 64Cu-NOTA-pertuzumab is an effective PET tracer for the non-invasive imaging of HER2 expression in vivo, rendering it a potential tracer for treatment monitoring and improved patient stratification.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Receptor ErbB-2/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/metabolismo , Anticuerpos Monoclonales Humanizados/farmacocinética , Línea Celular Tumoral , Transformación Celular Neoplásica , Radioisótopos de Cobre , Femenino , Compuestos Heterocíclicos con 1 Anillo/química , Humanos , Marcaje Isotópico , Ratones , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Radiometría , Distribución TisularRESUMEN
CD146 has been identified as an excellent biomarker for lung cancer as its overexpression in solid tumors has been linked to disease progression, invasion, and metastasis. Previously, our group described a positive correlation between 64Cu-labeled YY146 uptake and increased expression of CD146 in six human lung cancer cell lines using subcutaneous tumor models. In this study, we investigate a monoclonal antibody called YY146 for immunoPET imaging of CD146 in two intrapulmonary metastasis models of non-small cell lung cancer (NSCLC). The binding and immunoreactivity of the tracer were assessed by in vitro assays. Radiolabeling of YY146 with positron emitting Cu-64 (64Cu-NOTA-YY146) enabled PET imaging of intrapulmonary metastasis. Mice were intravenously injected with two million tumor cells, and CT imaging was used to verify the presence of lung metastases. 64Cu-NOTA-YY146 was injected into tumor-bearing mice, and animals were subjected to PET/CT imaging at 4, 24, and 48 h postinjection. Both the average and maximum lung PET signal intensities were quantified and compared between high and low CD146-expressing metastases. Further validation was accomplished through immunofluorescence imaging of resected tissues with CD31 and CD146. In flow cytometry, YY146 revealed strong binding to CD146 in H460 cells due to its high expression with minimal binding to CD146-low expressing H358 cells. Both YY146 and NOTA-YY146 showed similar binding, suggesting that NOTA conjugation did not elicit any negative effects on its binding affinity. Imaging of 64Cu-NOTA-YY146 in H460 tumor-bearing mice revealed rapid, persistent, and highly specific tracer accumulation. Uptake of 64Cu-NOTA-YY146 in the whole lung was calculated for H460 and H358 as 7.43 ± 0.38 and 3.95 ± 0.47% ID/g at 48 h postinjection (n = 4, p < 0.05), and the maximum lung signals were determined to be 13.85 ± 1.07 (H460) and 6.08 ± 0.73% ID/g (H358) at equivalent time points (n = 4, p < 0.05). To ensure the specificity of the tracer, a nonspecific antibody was injected into H460 tumor-bearing mice. Ex vivo biodistribution and immunofluorescence imaging validated the PET findings. In summary, 64Cu-NOTA-YY146 allowed for successful imaging of CD146-expressing intrapulmonary metastases of NSCLC in mice. This preliminary study provides evidence supporting the future clinical utilization of 64Cu-NOTA-YY146 for possible treatment monitoring of CD146-targeted therapy or improving patient stratification.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Imagen Molecular/métodos , Animales , Anticuerpos Monoclonales/química , Biomarcadores de Tumor/inmunología , Antígeno CD146/inmunología , Antígeno CD146/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Radioisótopos de Cobre , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Compuestos Heterocíclicos , Compuestos Heterocíclicos con 1 Anillo , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Trazadores Radiactivos , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on the surface of activated T cells and some tumor cells, and is the target of the clinically approved monoclonal antibody ipilimumab. In this study, we investigate specific binding of radiolabeled ipilimumab to CTLA-4 expressed by human non-small cell lung cancer cells in vivo using positron emission tomography (PET). Ipilimumab was radiolabeled with 64Cu (t1/2 = 12.7 h) through the use of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to formulate 64Cu-DOTA-ipilimumab. CTLA-4 expression in three non-small cell lung cancer (NSCLC) cell lines (A549, H460, and H358) was verified and quantified by Western blot and enzyme-linked immunosorbent assays (ELISA). A receptor binding assay was utilized to monitor the binding and internalization of 64Cu-DOTA-ipilimumab in the NSCLC cell lines. Next, the biodistribution of 64Cu-DOTA-ipilimumab was mapped by longitudinal PET imaging up to 48 h after injection. Ex vivo biodistribution and histological studies were employed to verify PET results. By in vitro analysis, CTLA-4 was found to be expressed on all three NSCLC cell lines with A549 and H358 showing the highest and lowest level of expression, respectively. PET imaging and quantification verified these findings as the tracer accumulated highest in the A549 tumor model (9.80 ± 0.22%ID/g at 48 h after injection; n = 4), followed by H460 and H358 tumors with uptakes of 9.37 ± 0.26%ID/g and 7.43 ± 0.05%ID/g, respectively (n = 4). The specificity of the tracer was verified by injecting excess ipilimumab in A549 tumor-bearing mice, which decreased tracer uptake to 6.90 ± 0.51%ID/g at 48 after injection (n = 4). Ex vivo analysis following the last imaging session also corroborated these findings. 64Cu-DOTA-ipilimumab showed enhanced and persistent accumulation in CTLA-4-expressing tissues, which will enable researchers further insight into CTLA-4 targeted therapies in the future.