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The combination of diagnostic and therapeutic functions in a single theranostic nanoagent generally requires the integration of multi-ingredients. Herein, a cytotoxic near-infrared (NIR) dye (IR-797) and its nanoassembly are reported for multifunctional cancer theranostics. The hydrophobic IR-797 molecules are self-assembled into nanoparticles, which are further modified with an amphiphilic polymer (C18PMH-PEG5000) on the surface. The prepared PEG-IR-797 nanoparticles (PEG-IR-797 NPs) possess inherent cytotoxicity from the IR-797 dye and work as a chemotherapeutic drug which induces apoptosis of cancer cells. The IR-797 NPs are found to have an ultrahigh mass extinction coefficient (444.3 L g-1 cm-1 at 797 nm and 385.9 L g-1 cm-1 at 808 nm) beyond all reported organic nanomaterials (<40 L g-1 cm-1 ) for superior photothermal therapy (PTT). In addition, IR-797 shows some aggregation-induced-emission (AIE) properties. Combining the merits of good NIR absorption, high photothermal energy conversion efficiency, and AIE, makes the PEG-IR-797 NPs useful for multimodal NIR AIE fluorescence, photoacoustic, and thermal imaging-guided therapy. The research exhibits the possibility of using a single ingredient and entity to perform multimodal NIR fluorescence, photoacoustic, and thermal imaging-guided chemo-/photothermal combination therapy, which may trigger wide interest from the fields of nanomedicine and medicinal chemistry to explore multifunctional theranostic organic molecules.
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Antineoplásicos/química , Nanomedicina Teranóstica/métodos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Técnicas Fotoacústicas/métodos , Fotoquimioterapia/métodos , Polímeros/químicaRESUMEN
The small molecule fluorescein is commonly used to guide the repair of cerebral spinal fluid leaks (CSFLs) in the clinic. We modified fluorescein so that it is also visible by positron emission tomography (PET). This probe was used to quantitatively track the fast distribution of small molecules in the CSF of rats. We tested this probe in models relevant to the clinical diagnosis and treatment of central nervous system (CNS) diseases that affect CSF flow. In this study, fluorescein was radiolabeled with fluorine-18 to produce Fc-AMBF3. [18/19F]-Fc-AMBF3 was introduced at trace quantities (13.2 nmols, 100 µCi) intrathecally (between L5 and L6) in rats to observe the dynamic distribution and clearance of small molecules in the CSF by both [18F]-PET and fluorescence (FL) imaging. Murine models were used to demonstrate the following utilities of Fc-AMBF3: (1) utility in monitoring the spontaneous CSFL repair of a compression fracture of the cribriform plate and (2) utility in quantifying CSF flow velocity during neurosurgical lumboperitoneal shunt placement. Fc-AMBF3 clearly delineated CSF-containing volumes based on noninvasive PET imaging and in ex vivo FL histology. In vivo morbidity (n = 16 rats, <2.7 mg/kg, 77 times the PET dose) was not observed. The clearance of the contrast agent from the CNS was rapid and quantitative (t1/2 = 33.8 ± 0.6 min by FL and t1/2 = 26.0 ± 0.5 min by PET). Fc-AMBF3 was cleared from the CSF through the vasculature and/or lymphatic system that supplies the cribriform plate and the temporal bone. Fc-AMBF3 can be used to diagnose CSFLs, image CSFL repair, and determine the CSF flow velocity in the CNS or through lumboperitoneal shunts by PET/FL imaging. In conclusion, Fc-AMBF3 PET imaging has been demonstrated to safely and dynamically quantitate CSF flow, diagnose fistulas associated with the CSF space, and approximate the clearance of small molecules in the CSF.
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Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Pérdida de Líquido Cefalorraquídeo/diagnóstico por imagen , Fluoresceína/farmacocinética , Colorantes Fluorescentes/farmacocinética , Radioisótopos de Flúor , Radiofármacos/farmacocinética , Animales , Línea Celular Tumoral , Enfermedades del Sistema Nervioso Central/cirugía , Líquido Cefalorraquídeo/diagnóstico por imagen , Pérdida de Líquido Cefalorraquídeo/cirugía , Derivaciones del Líquido Cefalorraquídeo/instrumentación , Derivaciones del Líquido Cefalorraquídeo/métodos , Modelos Animales de Enfermedad , Fluoresceína/administración & dosificación , Fluoresceína/química , Colorantes Fluorescentes/administración & dosificación , Colorantes Fluorescentes/química , Humanos , Inyecciones Espinales , Masculino , Tomografía de Emisión de Positrones , Radiofármacos/administración & dosificación , Radiofármacos/química , Ratas , Distribución Tisular , Pruebas de Toxicidad , Cirugía Asistida por Video/métodosRESUMEN
The authors wish to make the following corrections to this paper [...].
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An effective tumoral delivery system should show minimal removal by the reticuloendothelial system (RES), promote tumor uptake and penetration, and minimize on-site clearance. This study reports the design and synthesis of advanced self-assembling peptide nanofiber precursor (NFP) analogues. The peptidic nature of NFP offers the design flexibility for on-demand customization with imaging agents and surface charges while maintaining a set size, allowing for real-time monitoring of kinetic and dynamic tumoral delivery by multimodal fluorescence/positron emission tomography/computed tomography (fluo/PET/CT) imaging, for formulation optimization. The optimized glutathione (GSH)-NFP displays a reduced capture by the RES as well as excellent tumor targeting and tissue invasion properties compared to naive NFP. Inside a tumor, GSH-NFP can structurally transform into ten times larger interfibril networks, serving as in situ depot that promotes weeks-long local retention. This nanofiber, which can further be designed to release the active pharmacophores within a tumor microenvironment, displays a superior therapeutic efficacy for inhibiting disease progression and improving the survival of animals bearing triple-negative breast cancer tumors compared to free drug and liposome formulation of the drug, in addition to a favorable toxicity profile.
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Cell fate is a concept used to describe the differentiation and development of a cell in its organismal context over time. It is important in the field of regenerative medicine, where stem cell therapy holds much promise but is limited by our ability to assess its efficacy, which is mainly due to the inability to monitor what happens to the cells upon engraftment to the damaged tissue. Currently, several imaging modalities can be used to track cells in the clinical setting; however, they do not satisfy many of the criteria necessary to accurately assess several aspects of cell fate. In recent years, reporter genes have become a popular option for tracking transplanted cells, via various imaging modalities in small mammalian animal models. This review article examines the reporter gene strategies used in imaging modalities such as MRI, SPECT/PET, Optoacoustic and Bioluminescence Imaging. Strengths and limitations of the use of reporter genes in each modality are discussed.
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Rastreo Celular/métodos , Diagnóstico por Imagen/métodos , Genes Reporteros/genética , Células Madre/patología , Animales , Diferenciación Celular/genética , Humanos , Medicina Regenerativa/métodos , Investigación con Células Madre , Trasplante de Células Madre/métodosRESUMEN
The novel synthesis of a dual-modality, pentamethine cyanine (Cy5) fluorescent, 18F positron emission tomography (PET) imaging probe is reported. The probe shows a large extinction coefficient and large quantum yield in the biologically transparent, near-infrared window (650-900 nm) for in vivo fluorescent imaging. This fluorophore bears the isotope, 18F, giving a 18F-PET/near-infrared fluorescent (NIRF), bi-modal imaging probe, that combines the long-term stability of NIRF and the unlimited penetration depth of PET imaging. The bi-modal probe is labeled with 18F in a quick, one-step reaction, which is important in working with the rapid decay of 18F. The bi-modal probe bears a free carboxyl group, highlighting a PET/NIRF synthon that can be conjugated onto many advanced biomolecules for biomarker-specific in vivo dual-modal PET/NIR tumor imaging, confocal histology, and utility in multi-fluorophore, fluorescence-guided surgery. Its potential in vivo biocompatibility is explored in a quick proof-of-principal in vivo study. The dye is delivered to A549 xenograft flank-tumors to generate PET and NIRF signals at the tumor site. The tumor distribution is confirmed in ex vivo gamma counting and imaging. Pentamethine cyanine (Cy5) has the ability to preferentially accumulate in tumor xenografts. We substitute the PET/NIRF probe for Cy5, and explore this phenomenon.
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Carbocianinas , Colorantes Fluorescentes , Radioisótopos de Flúor , Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones , Espectroscopía Infrarroja Corta , Animales , Carbocianinas/química , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Colorantes Fluorescentes/química , Radioisótopos de Flúor/química , Xenoinjertos , Humanos , Ratones , Imagen Multimodal , Neoplasias/metabolismo , Neoplasias/patología , Tomografía de Emisión de Positrones/métodos , Espectroscopía Infrarroja Corta/métodosRESUMEN
Thanks to the recent advances in the development of chemotherapeutics, the morbidity and mortality of many cancers has decreased significantly. However, compared to oncology in general, the field of neuro-oncology has lagged behind. While new molecularly targeted chemotherapeutics have emerged, the impermeability of the blood-brain barrier (BBB) renders systemic delivery of these clinical agents suboptimal. To circumvent the BBB, novel routes of administration are being applied in the clinic, ranging from intra-arterial infusion and direct infusion into the target tissue (convection enhanced delivery (CED)) to the use of focused ultrasound to temporarily disrupt the BBB. However, the current system depends on a "wait-and-see" approach, whereby drug delivery is deemed successful only when a specific clinical outcome is observed. The shortcomings of this approach are evident, as a failed delivery that needs immediate refinement cannot be observed and corrected. In response to this problem, new theranostic agents, compounds with both imaging and therapeutic potential, are being developed, paving the way for improved and monitored delivery to central nervous system (CNS) malignancies. In this review, we focus on the advances and the challenges to improve early cancer detection, selection of targeted therapy, and evaluation of therapeutic efficacy, brought forth by the development of these new agents.
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Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Imagen Molecular , Terapia Molecular Dirigida , Animales , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias del Sistema Nervioso Central/metabolismo , Ensayos Clínicos como Asunto , Portadores de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Humanos , Imagen Molecular/métodos , Resultado del TratamientoRESUMEN
New protecting group chemistry is used to greatly simplify imaging probe production. Temperature and organic solvent-sensitive biomolecules are covalently attached to a biotin-bearing dioxaborolane, which facilitates antibody immobilization on a streptavidin-agarose solid-phase support. Treatment with aqueous fluoride triggers fluoride-labeled antibody release from the solid phase, separated from unlabeled antibody, and creates [(18)F]-trifluoroborate-antibody for positron emission tomography and near-infrared fluorescent (PET/NIRF) multimodality imaging. This dioxaborolane-fluoride reaction is bioorthogonal, does not inhibit antigen binding, and increases [(18)F]-specific activity relative to solution-based radiosyntheses. Two applications are investigated: an anti-epithelial cell adhesion molecule (EpCAM) monoclonal antibody (mAb) that labels prostate tumors and Cetuximab, an anti-epidermal growth factor receptor (EGFR) mAb (FDA approved) that labels lung adenocarcinoma tumors. Colocalized, tumor-specific NIRF and PET imaging confirm utility of the new technology. The described chemistry should allow labeling of many commercial systems, diabodies, nanoparticles, and small molecules for dual modality imaging of many diseases.
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Compuestos de Boro/química , Colorantes Fluorescentes/química , Radioisótopos de Flúor , Tomografía de Emisión de Positrones/métodos , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Cetuximab/metabolismo , Humanos , Ratones , Imagen Óptica , Radioquímica , Estreptavidina/metabolismoRESUMEN
OBJECTIVE: The purpose of this article is to summarize advances in PET fluorescence resolution, agent design, and preclinical imaging that make a growing case for clinical PET fluorescence imaging. CONCLUSION: Existing SPECT, PET, fluorescence, and MRI contrast imaging techniques are already deeply integrated into the management of cancer, from initial diagnosis to the observation and management of metastases. Combined positron-emitting fluorescent contrast agents can convey new or substantial benefits that improve on these proven clinical contrast agents.
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Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Espectrometría de Fluorescencia/métodos , Espectroscopía Infrarroja Corta/métodos , Animales , Biomarcadores de Tumor/análisis , Medios de Contraste , HumanosRESUMEN
Organotrifluoroborates solvolyze in water at rates that vary over five orders of magnitude. The negative logarithm of the solvolytic rate constant, pk(B-F), correlates exceptionally well with the pKa of the analogous carboxylic acid (R(2) = 0.984). This unforeseen correlation may be of predictive value for several applications including Suzuki-Miyaura cross-coupling reactions and the design of (18)F-organotrifluoroborate radioprosthetic groups.
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Boratos/química , Ácidos Carboxílicos/química , Radioisótopos de Flúor/química , Reactivos de Enlaces Cruzados/química , Solubilidad , AguaRESUMEN
Fluorescent probes in the near-infrared (NIR) range have immense potential to improve observation of positive margins, lymph nodes, and nerves in prostatectomy. Development of fluorescent dyes and mechanisms of cellular uptake paved the way for the current emerging technologies. However, intracellular transport of fluorophores proved to be logistically challenging with respect to intraoperative deployment. Peptide-based probes with high specificity for nerves enabled broader and more rapid labeling. Key features of the ideal probe include selectivity, minimal background noise, safety, and low cost. Human neuropeptide 401 (HNP401) and oxazine-based probes perform well in these categories. As for tumor-specific labeling, prostate specific membrane antigen is relatively selective for the prostate and can be conjugated to a fluorophore. NIR spectrum emission is an ideal range for clinical imaging use, as fluorescence occurs outside the field of visible light, and tissue optical properties diverge significantly at the visible-NIR transition. Indocyanine, carbocyanine, and fluorescein derivatives are common fluorophore conjugates for the probes. Finally, to harness the power of fluorescence intraoperatively, the surgeon must look through a specialized lens. Multiphoton microscopy, optical coherence tomography, and confocal laser endomicroscopy have emerged as frontrunners in this arena. As with any evolving technology, ongoing research is expanding the applications of fluorescent intraoperative imaging in prostate surgery. Innovations in camera technology, dye selection, and image processing are refining the technique's capabilities. A core challenge of these technologies translating into the operating room relates to size and the ability to view objects at vastly different magnifications. Dual modality zoom settings are promising solutions. Furthermore, interdisciplinary collaboration between surgeons, imaging specialists, and researchers continues to drive advancements. In conclusion, fluorescent intraoperative imaging has the potential to usher in a new era of precision and safety in prostate surgery.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Prostatectomía/métodos , Próstata/diagnóstico por imagen , Próstata/cirugía , Colorantes Fluorescentes , FluoresceínaRESUMEN
BACKGROUND: The non-invasive imaging of leukocyte trafficking to assess inflammatory areas and monitor immunotherapy is currently generating great interest. There is a need to develop more robust cell labelling and imaging approaches to track living cells. Positron emission tomography (PET), a highly sensitive molecular imaging technique, allows precise signals to be produced from radiolabelled moieties. Here, we developed a novel leukocyte labelling approach with the PET radioisotope zirconium-89 (89Zr, half-life of 78.4 h). Experiments were carried out using human leukocytes, freshly isolated from whole human blood. RESULTS: The 89Zr-leukocyte labelling efficiency ranged from 46 to 87% after 30-60 min. Radioactivity concentrations of labelled cells were up to 0.28 MBq/1 million cells. Systemically administered 89Zr-labelled leukocytes produced high-contrast murine PET images at 1 h-5 days post injection. Murine biodistribution data showed that cells primarily distributed to the lung, liver, and spleen at 1 h post injection, and are then gradually trafficked to liver and spleen over 5 days. Histological analysis demonstrated that exogenously 89Zr-labelled human leukocytes were present in the lung, liver, and spleen at 1 h post injection. However, intravenously injected free [89Zr]Zr4+ ion showed retention only in the bone with no radioactivity in the lung at 5 days post injection, which implied good stability of radiolabelled leukocytes in vivo. CONCLUSIONS: Our study presents a stable and generic radiolabelling technique to track leukocytes with PET imaging and shows great potential for further applications in inflammatory cell and other types of cell trafficking studies.
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In addition to its role in the regulation of sex-related processes, 17ß-estradiol (E2) participates in the prevention and treatment of cardiovascular diseases via nongenomic pathways mediated by estrogen receptors (ER-α) located in the cell membrane. To achieve specific nongenomic activity of E2, we linked E2 (4.4 mol %) to chitosan-phosphorylcholine (CH-PC) (20 mol % PC). Injections of ER-α solutions (5 to 100 nmol L(-1)) over rehydrated CH-PC-E2 thin films led to permanent adsorption of ER-α to the film surface, as detected by quartz crystal microbalance with dissipation (QCM-D). However, ER-α did not bind onto CH-PC-E2 films formed in situ and never dried. X-ray photoelectron spectroscopy (XPS) analysis of spin-cast CH-PC-E2 films revealed significant E2 enrichment of the topmost section of the film, attributed to the preferential migration of E2 toward the film/air interface upon drying. Mechanical analysis of CH-PC-E2 films in the frequency domain probed by QCM-D indicated that rehydrated films behave as an entangled network with junction points formed by self-assembly of hydrophobic E2 moieties and by ion pairing among PC groups, whereas films formed in situ are entangled polymer solutions with temporary junctions. The structural analysis presented offers useful guidelines for the study of amphiphilic biomacromolecules designed for therapeutic use as thin films.
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Materiales Biocompatibles/síntesis química , Estradiol/química , Polisacáridos/química , Quitosano/química , Interacciones Hidrofóbicas e Hidrofílicas , Microscopía de Fuerza Atómica , Fosforilcolina/química , Espectroscopía de Fotoelectrones/métodos , Polímeros/síntesis química , Tecnicas de Microbalanza del Cristal de Cuarzo/métodos , Propiedades de SuperficieRESUMEN
Prostate-specific membrane antigen (PSMA) - based radiopharmaceuticals are promising for the evaluation of PSMA-positive non-prostate cancers. In this case study, 18F-BF3-Cy3-ACUPA and 68Ga-PSMA positron emission tomography/magnetic resonance imaging (PET/MRI) were compared in a patient with metastatic colon cancer. Both 18F-BF3-Cy3-ACUPA and 68Ga-PSMA PET/MRI showed biopsy-proven metastatic left external iliac adenopathy, highlighting the feasibility of PSMA uptake in PET/MRI of metastatic nodal disease from colon cancer. Along with imaging evaluation, PSMA-based radiopharmaceuticals may also be used as a surrogate imaging tracer for potential theranostic applications using alpha or beta emitters in the context of PSMA-directed radiopharmaceutical therapy in advanced and progressive colorectal cancer.
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Neoplasias del Colon , Neoplasias de la Próstata , Neoplasias del Colon/diagnóstico por imagen , Isótopos de Galio , Radioisótopos de Galio , Glutaratos , Humanos , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , RadiofármacosRESUMEN
Correction for 'Facile synthesis of near-infrared bodipy by donor engineering for in vivo tumor targeted dual-modal imaging' by Feifei An et al., J. Mater. Chem. B, 2021, 9, 9308-9315, DOI: 10.1039/D1TB01883C.
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Targeted radionuclide therapy has emerged as a promising and potentially curative strategy for high-grade prostate cancer. However, limited data are available on efficacy, quality of life, and pretherapeutic biomarkers. Here, we highlight the case of a patient with prostate-specific membrane antigen (PSMA)-positive metastatic castrate-resistant prostate cancer who displayed complete response to 225Ac-PSMA-617 after having been resistant to standard-of-care therapy, then initially partially responsive but later resistant to subsequent immunotherapy, and resistant to successive 177Lu-PSMA-617. In addition, the patient's baseline germline mutation likely predisposed him to more aggressive disease.
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Self-labeling proteins have revolutionized super-resolution and sensor imaging. Tags recognize a bioorthogonal substrate for covalent attachment. We show the small Ultra-Red Fluorescent Protein (smURFP) is a self-labeling protein. The substrate is fluorogenic, fluoresces when attached, and quenches fluorescent cargo. The smURFP-tag has novel properties for tool development.
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Bodipy is one of the most popular dyes for bioimaging, however, a complicated synthetic protocol is needed to create and isolate ideal near-infrared (NIR) emissive Bodipy derivatives for optical bioimaging. It is noticed that the donor species impact the wavelength when the π-conjugation system of green light emissive Bodipy is elongated via a one-step reaction. Herein, several Bodipy dyes bearing different common donors are synthesized. Their optical properties confirm that both absorption and emission peaks of the synthesized Bodipy could be tuned to NIR wavelength by using stronger donors via a facile reaction. The synthesized monocarboxyl Bodipy could conjugate with aminated PEG to yield an amphiphilic polymer, which further self-assembles into a NIR nanoparticle (NP). The NIR NP exhibits preferential tumor accumulation via the enhanced permeation and retention (EPR) effect, making it useful for tumor diagnosis by both fluorescence imaging and photoacoustic tomography.
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Adenocarcinoma del Pulmón/diagnóstico por imagen , Compuestos de Boro/síntesis química , Ingeniería Química , Neoplasias/diagnóstico por imagen , Células A549 , Animales , Humanos , Ratones , Ratones Desnudos , Neoplasias Experimentales/diagnóstico por imagenRESUMEN
Adoptive cell transfer of targeted chimeric antigen receptor (CAR) T cells has emerged as a highly promising cancer therapy. The pharmacodynamic action or CAR T cells is closely related to their pharmacokinetic profile; because of this as well as the risk of non-specific action, it is important to monitor their biodistribution and fate following infusion. To this end, we developed a dual-modal PET/near infrared fluorescent (NIRF) nanoparticle-based imaging agent for non-genomic labeling of human CAR T cells. Since the PET/NIRF nanoparticles did not affect cell viability or cytotoxic functionality and enabled long-term whole-body CAR T cell tracking using PET and NIRF in an ovarian peritoneal carcinomatosis model, this platform is a viable imaging technology to be applied in other cancer models.