RESUMEN
Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt's lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38-targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr-89 and Lu-177 for theranostic applications. As the diagnostic component, the Zr-89-labeled mAb is highly specific in delineating CD38-positive lymphoma via positron emission tomography (PET) imaging, while the Lu-177-labeled mAb serves well as the therapeutic component to suppress tumor growth after a one-time administration. These results strongly suggest that CD38 is a lymphoma-specific marker and prove that 89Zr/177Lu-labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38-targeted theranostics may be of significant help in lymphoma patient stratification and management.
Asunto(s)
ADP-Ribosil Ciclasa 1/inmunología , Anticuerpos Monoclonales/farmacología , Lutecio/farmacocinética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Glicoproteínas de Membrana/inmunología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Medicina de Precisión/métodos , Radioisótopos/farmacocinética , Circonio/farmacocinética , ADP-Ribosil Ciclasa 1/metabolismo , Animales , Anticuerpos Monoclonales/farmacocinética , Línea Celular Tumoral , Humanos , Factores Inmunológicos/farmacocinética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Glicoproteínas de Membrana/metabolismo , Ratones Endogámicos BALB C , Ratones SCID , Radiofármacos/farmacocinética , Radiofármacos/farmacología , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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
Programmed death protein 1 and programmed death-ligand 1 (PD-1/PD-L1) have been widely studied as one of the most critical immune check-point pairs in the cancer microenvironment. In breast cancer (BrCa), the expression of PD-L1 is regarded as a determinant biomarker for patient stratification and prediction of inhibition response. Quantitative positron emission tomography (PET) imaging of PD-L1 expression in tumors using a therapeutic antibody in the clinic seems to be a promising approach that can complement conventional histopathological methods and overcome several issues, such as the tumor heterogeneities, sampling representativeness and clear differentiation of positive and negative results. In this study, we synthesized and evaluated 89Zr-labeled avelumab (Ave) for the in vivo characterization of PD-L1 expression in BrCa. Confocal imaging of BrCa cells and flow cytometry were employed to evaluate PD-L1 expression in MDA-MB-231 cells. The intact human monoclonal antibody targeting PD-L1, i.e., Ave, was conjugated to p-SCN-Deferoxamine (Df) and labeled with 89Zr. After intravenous injection of 89Zr-Df-avelumab (89Zr-Df-Ave), PET imaging of MDA-MB-231 tumor-bearing mice, with or without blocking, was performed. High PD-L1 expression of MDA-MB-231 cells was confirmed by in vitro immuno-fluorescent staining and flow cytometry. PET imaging indicated the peak uptake of 89Zr-Df-Ave in the tumor (6.4±1.0 %ID/g), spleen (10.2±0.7 %ID/g) and lymph nodes (6.9±1.0 %ID/g) at 48 h after injection (n=4). Blocking study using unlabeled Ave could reduce the tracer uptake in these tissues (5.2±1.0 %ID/g in the tumor, 4.9±0.5 %ID/g in the spleen and 5.8±1.1 %ID/g in lymph nodes at 48 h, n=4), which demonstrated the specificity of 89Zr-Df-Ave. Biodistribution study and immuno-fluorescent staining were consistent with the quantitative data from PET imaging. Herein, we offer the evidence supporting the value of immuno-PET imaging using 89Zr-Df-Ave for non-invasive characterization of PD-L1 expression in BrCa and the applicability of this tracer in BrCa for treatment evaluation after immunotherapy.
RESUMEN
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.
Asunto(s)
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
CD38 is expressed on the surface of many immune cells, which are closely associated with antitumor immunity and immune tolerance of tumor cells. Therefore, monitoring CD38 expression has gained great attention for tracking the progression of tumors and cancer treatment. Herein, we aim to develop a PET tracer using an anti-CD38 monoclonal antibody (daratumumab) to monitor CD38 expression in hepatocellular carcinoma (HCC). In this study, daratumumab was radiolabeled with 64Cu (t1/2=12.7 h) to obtain 64Cu-NOTA-daratumumab. Relative CD38 expression in HepG2 and Huh7 HCC cell lines was assessed using western blot. The specificity of 64Cu-NOTA-daratumumab to both cell lines was examined using an in vitro cell-binding assay. PET imaging in subcutaneous models of HCC was performed to evaluate the capability and specificity of 64Cu-NOTA-daratumumab to target CD38 in vivo. Region-of-interest analysis and ex vivo biodistribution were performed to verify the tracer targeting capability of CD38. Through cellular studies of two HCC cell lines, CD38 expression was found to be higher in HepG2 and minimal in Huh7 cells. 64Cu-NOTA-daratumumab showed relatively high affinity to CD38 (Ka=18.21 ± 1.74 nM), while the affinity of Huh7 was in the micromolar range for daratumumab binding to the cells (Ka=3.98 ± 0.87 µM). At 48 h post-injection, PET imaging of subcutaneous models with 64Cu-NOTA-daratumumab revealed tumor uptakes of 12.23 ± 2.4 and 2.7 ± 1.2 %ID/g for HepG2 and Huh7, respectively (n=4), which correlated well with relative CD38 expression of the cells. Moreover, the 64Cu-NOTA-IgG nonspecific analogue showed a significantly lower uptake in HepG2 subcutaneous model in mice, suggesting a specific binding of daratumumab with CD38 in vivo. Our cellular studies and PET imaging confirmed the capability and specificity of 64Cu-NOTA-daratumumab for the imaging of CD38 in murine models of HCC. This study supports our claim that 64Cu-NOTA-daratumumab is an effective PET tracer for the non-invasive evaluation of CD38 expression and sensitive detection of CD38-positive tumor lesions in HCC.
RESUMEN
Oxidative stress is one of the important mechanisms in cerebral ischemia/reperfusion (I/R) injury. Antioxidants with high brain accumulation are highly desired to help prevent cerebral I/R injury. Herein, intrathecal injection of polyoxometalate (POM) nanoclusters as nano-antioxidants with preferential brain uptake were applied for neuronal protection in cerebral I/R injury. Using powerful positron emission tomography imaging, the uptake of nano-antioxidants in the brain was non-invasively and real-timely monitored. Our results demonstrated that POM nanoclusters rapidly reached the ischemic penumbra after intrathecal injection and effectively scavenged reactive oxygen species (ROS) for inhibiting oxidative stress. The infarct size was reduced, and neurological function was restored in cerebral I/R injury rat models. As a proof-of-concept, the intrathecal injection of nano-antioxidants is an excellent therapeutic strategy to ameliorate cerebral I/R injury.
Asunto(s)
Antioxidantes/farmacología , Isquemia Encefálica/tratamiento farmacológico , Nanopartículas/química , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/tratamiento farmacológico , Compuestos de Tungsteno/farmacología , Animales , Antioxidantes/administración & dosificación , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/metabolismo , Modelos Animales de Enfermedad , Inyecciones Espinales , Imagen por Resonancia Magnética , Nanopartículas/administración & dosificación , Neuronas/efectos de los fármacos , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/diagnóstico por imagen , Daño por Reperfusión/metabolismo , Compuestos de Tungsteno/administración & dosificaciónRESUMEN
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
Pertuzumab is clinically employed in the treatment of cancers over-expressing human epidermal growth factor receptor 2 (HER2). Herein, we developed dual-labeled pertuzumab with a radionuclide (89Zr) and a near-infrared fluorophore (IRDye 800CW) to investigate the feasibility of utilizing dual-labeled monoclonal antibodies (mAbs) with numerous imaging modalities for preoperative imaging and image-guided surgery in ovarian cancer models. MAbs were dually-labeled with 89Zr and IRDye 800CW to generate 89Zr-Df-pertuzumab-800CW or 89Zr-Df-IgG-800CW. Serial positron emission tomography (PET) and near-infrared fluorescence (NIRF) images were acquired up to 72 hours after injection of dual-labeled mAbs to map the tracers' biodistributions. After the last time point, image-guided tumor resection was executed using different modalities (NIRF, Cerenkov luminescence [CL], and ß particle imaging) and ex vivo studies including biodistribution assays and histology analysis were performed to confirm the in vivo imaging data. SKOV3 ovarian cancer cells showed high expression of HER2 and pertuzumab conjugated with Df and IRDye 800CW maintained its binding affinity for these cells. For PET imaging in subcutaneous xenograft ovarian cancer models, 89Zr-Df-pertuzumab-800CW showed a significantly higher tumor-to-muscle ratio compared to the nonspecific 89Zr-Df-IgG-800CW from 24 hours after injection through the last time point (72 h: 30.7 ± 7.4 vs. 7.5 ± 1.8, P < 0.01, n = 3-4). During image-guided surgery, three imaging modalities including NIRF, CL, and ß particle imaging could detect ovarian cancer in both subcutaneous and orthotopic models and each exhibited its own imaging characteristics. In addition, ex vivo imaging and biodistribution studies as well as histology analysis corroborated the in vivo imaging results. Therefore, we concluded that this single radiolabeled tracer can provide all-in-one contrast for multiple imaging modalities. The dual-labeled mAbs may hold promise to be employed for image-guided tumor surgery as well as diagnosis and staging through balancing out the strengths and weaknesses of various modalities such as PET/CT, NIRF, CL, and ß particle imaging.
RESUMEN
Since diabetes is becoming a global epidemic, there is a great need to develop early ß-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic ß-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of ß-cell mass (BCM) and/or impairment of the function of individual ß-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic ß-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. ß-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted ß-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging ß-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field.
Asunto(s)
Diabetes Mellitus/diagnóstico por imagen , Imagen Molecular , Animales , Anticuerpos/uso terapéutico , Medios de Contraste/uso terapéutico , Diabetes Mellitus/inmunología , Receptor del Péptido 1 Similar al Glucagón , Humanos , Células Secretoras de Insulina/inmunología , Manganeso/uso terapéutico , Receptores de Sulfonilureas , Proteínas de Transporte Vesicular de MonoaminasRESUMEN
For melanoma resistant to molecularly targeted therapy and immunotherapy, new treatment strategies are urgently needed. A molecularly targeted theranostic pair may thus be of importance, where the diagnostic probe facilitates patient stratification and the therapeutic companion treats the selected cases. For this purpose, flow cytometry is used to assess the CD146 level in melanoma cells. Based on YY146, a CD146-specific monoclonal antibody, an imaging probe 89Zr-Df-YY146 is synthesized and its diagnostic performance is evaluated by positron emission tomography (PET) imaging. Furthermore, a photoimmunotherapy (PIT) agent IR700-YY146 is developed and the therapeutic effect of IR700-YY146 PIT is assessed comprehensively. CD146 is highly expressed in A375 and SK-MEL-5 cells. 89Zr-Df-YY146 PET readily detects CD146-positive A375 melanomas. Tumor accumulation of 89Zr-Df-YY146 peaks at 72 h with an uptake value of 26.48 ± 3.28%ID g-1, whereas the highest uptake of the nonspecific 89Zr-Df-IgG is 4.80 ± 1.75%ID g-1. More importantly, IR700-YY146 PIT effectively inhibits the growth of A375 tumors, owing to production of reactive oxygen species, decreased glucose metabolism, and reduced expression of CD146. To conclude, 89Zr-Df-YY146 and IR700-YY146 are a promising theranostic pair with the former revealing CD146 expression in melanoma as a PET probe and the latter specifically treating CD146-positive melanoma as an effective PIT agent.
RESUMEN
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
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.
Asunto(s)
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
Imaging of immunotherapy targets using positron emission tomography (PET) can allow for noninvasive monitoring of their dynamic expression and may allow for patient stratification in the future. Therefore, two tracers targeting CTLA-4, one a full antibody and the other a F(ab')2 fragment, were radiolabeled with 64Cu and validated in humanized mouse models. Ipilimumab was digested to develop ipilimumab-F(ab')2, and both the intact antibody and the fragment were conjugated with NOTA to chelate 64Cu for PET. The tracers were administered to both control NBSGW mice and humanized mice (PBL mice, engrafted with human peripheral blood lymphocytes), and PET was conducted out to 48 h post-injection. PET region-of-interest analysis, ex vivo biodistribution studies, and tissue staining were used to confirm that the tracers specifically accumulated in CTLA-4+ tissues. Following injection of tracers (n = 3-5 per group), specific uptake was noted in the salivary gland tissues of the humanized mice. This uptake, a result of graft-versus-host disease onset, was proven to be due to human T-cells through staining of the tissues for human CD3 and CTLA-4. 64Cu-NOTA-ipilimumab demonstrated the highest absolute uptake in the salivary glands of PBL mice, peaking at 7.00 ± 2.19 %ID/g. In contrast, 64Cu-NOTA-ipilimumab-F(ab')2 uptake was 2.40 ± 0.86 %ID/g at the same time point. However, the F(ab')2 agent cleared from circulation more quickly than the intact antibody, providing higher salivary gland-to-blood ratios, which reached 1.78 ± 0.72 at 48 h post-injection, compared to 64Cu-NOTA-ipilimumab at 1.19 ± 0.49. Uptake of the tracers in the salivary glands of control mice, and the nonspecific tracer in the PBL mice, was lower at all time points as well. PET imaging with both 64Cu-NOTA-ipilimumab and 64Cu-NOTA-ipilimumab-F(ab')2 was able to localize CTLA-4+ tissues. These tracers may thus help elucidate the mechanisms of response to CTLA-4-targeted checkpoint immunotherapy treatments.
RESUMEN
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.
Asunto(s)
Colorantes Fluorescentes/química , Nanopartículas/química , Tomografía de Emisión de Positrones , Humanos , Imagen Multimodal , NanomedicinaRESUMEN
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
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
Overexpression and/or mutations of the receptor tyrosine kinase (RTK) subfamilies, such as epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), are closely associated with tumor cell growth, differentiation, proliferation, apoptosis, and cellular invasiveness. Monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKI) specifically inhibiting these RTKs have shown remarkable success in improving patient survival in many cancer types. However, poor response and even drug resistance inevitably occur. In this setting, the ability to detect and visualize RTKs with noninvasive diagnostic tools will greatly refine clinical treatment strategies for cancer patients, facilitate precise response prediction, and improve drug development. Positron emission tomography (PET) agents using targeted radioactively labeled antibodies have been developed to visualize tumor RTKs and are changing clinical decisions for certain cancer types. In the present review, we primarily focus on PET imaging of RTKs using radiolabeled antibodies with an emphasis on the clinical applications of these immunoPET probes. Mol Cancer Ther; 17(8); 1625-36. ©2018 AACR.
Asunto(s)
Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Humanos , Ratones , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Manganese-based nanoparticles (NPs) have recently attracted much attention in the field of biomedical imaging due to their impressive enhanced T1 contrast ability. Although the reported manganese-based NPs have exhibited good imaging capabilities as contrast agents, it is still urgent to develop novel multifunctional manganese-based imaging probes for future biomedical imaging, especially PET/MRI probes. Herein, we present chelator-free zirconium-89 (89Zr, t1/2: 78.4 h) labeling of manganese oxide NPs (Mn3O4@PEG) with â¼78% labeling yield and good stability. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies non-invasively assessed the biodistribution patterns of the NPs and the feasibility of in vivo dual-modality imaging and lymph-node mapping. Since Mn3O4 NPs exhibited desirable properties for enhanced T1 imaging and the simplicity of chelator-free radiolabeling, [89Zr]Mn3O4@PEG NPs offer a novel, simple, safe and accurate nanoplatforms for future precise cancer imaging and diagnosis.
Asunto(s)
Nanopartículas , Imagen por Resonancia Magnética , Compuestos de Manganeso , Óxidos , Tomografía de Emisión de Positrones , Radioisótopos , Distribución Tisular , CirconioRESUMEN
The rapidly evolving field of cancer immunotherapy recently saw the approval of several new therapeutic antibodies. Several cell therapies, for example, chimeric antigen receptor-expressing T cells (CAR-T), are currently in clinical trials for a variety of cancers and other diseases. However, approaches to monitor changes in the immune status of tumors or to predict therapeutic responses are limited. Monitoring lymphocytes from whole blood or biopsies does not provide dynamic and spatial information about T cells in heterogeneous tumors. Positron emission tomography (PET) imaging using probes specific for T cells can noninvasively monitor systemic and intratumoral immune alterations during experimental therapies and may have an important and expanding value in the clinic.