RESUMEN
Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n = 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response.
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Hipertermia Inducida , Nanopartículas de Magnetita , Compuestos Férricos , Humanos , Hipertermia , Campos Magnéticos , MagnetismoRESUMEN
Photoacoustic imaging combines both excellent spatial resolution with high contrast and specificity, without the need for patients to be exposed to ionizing radiation. This makes it ideal for the study of physiological changes occurring during tumorigenesis and cardiovascular disease. In order to fully exploit the potential of this technique, new exogenous contrast agents with strong absorbance in the near-infrared range, good stability and biocompatibility, are required. In this paper, we report the formulation and characterization of a novel series of endogenous contrast agents for photoacoustic imaging in vivo. These contrast agents are based on a recently reported series of indigoid π-conjugated organic semiconductors, coformulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, to give semiconducting polymer nanoparticles of about 150 nm diameter. These nanoparticles exhibited excellent absorption in the near-infrared region, with good photoacoustic signal generation efficiencies, high photostability, and extinction coefficients of up to three times higher than those previously reported. The absorption maximum is conveniently located in the spectral region of low absorption of chromophores within human tissue. Using the most promising semiconducting polymer nanoparticle, we have demonstrated wavelength-dependent differential contrast between vasculature and the nanoparticles, which can be used to unambiguously discriminate the presence of the contrast agent in vivo.
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Medios de Contraste/química , Imagen Molecular/métodos , Nanopartículas/química , Técnicas Fotoacústicas/métodos , Vasos Sanguíneos/diagnóstico por imagen , Humanos , Polímeros/química , Semiconductores , Espectroscopía Infrarroja CortaRESUMEN
BACKGROUND: Non-invasive measures of tumour vascular perfusion are desirable, in order to assess response to vascular targeting (or modifying) therapies. In this study, hepatic arterial spin labelling (ASL) magnetic resonance imaging (MRI) was investigated to measure acute changes in perfusion of colorectal cancer in the liver, in response to vascular disruption therapy with OXi4503. METHODS: SW1222 and LS174T tumours were established in the liver of MF1 nu/nu mice via intrasplenic injection. Perfusion and R2(*) MRI measurements were acquired with an Agilent 9.4T horizontal bore scanner, before and at 90 min after 40 mg kg(-1) OXi4503. RESULTS: A significant decrease in SW1222 tumour perfusion was observed (-43±33%, P<0.005). LS174T tumours had a significantly lower baseline level of perfusion. Intrinsic susceptibility MRI showed a significant increase in R2(*) in LS174T tumours (28±25%, P<0.05). An association was found between the change in tumour perfusion and the proximity to large vessels, with pre-treatment blood flow predictive of subsequent response. Histological evaluation confirmed the onset of necrosis and evidence of heterogeneous response between tumour deposits. CONCLUSIONS: Hepatic ASL-MRI can detect acute response to targeted tumour vascular disruption entirely non-invasively. Hepatic ASL of liver tumours has potential for use in a clinical setting.
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Arteria Hepática/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Hígado/patología , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Femenino , Angiografía por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Ratones , Ratones Desnudos , Marcadores de SpinRESUMEN
BACKGROUND: Solid tumours can undergo cycles of hypoxia, followed by reoxygenation, which can have significant implications for the success of anticancer therapies. A need therefore exists to develop methods to aid its detection and to further characterise its biological basis. We present here a novel method for decomposing systemic and tumour-specific contributions to fluctuations in tumour deoxyhaemoglobin concentration, based on magnetic resonance imaging measurements. METHODS: Fluctuations in deoxyhaemoglobin concentration in two tumour xenograft models of colorectal carcinoma were decomposed into distinct contributions using independent component analysis. These components were then correlated with systemic pulse oximetry measurements to assess the influence of systemic variations in blood oxygenation in tumours, compared with those that arise within the tumour itself (tumour-specific). Immunohistochemical staining was used to assess the physiological basis of each source of fluctuation. RESULTS: Systemic fluctuations in blood oxygenation were found to contribute to cycling hypoxia in tumours, but tumour-specific fluctuations were also evident. Moreover, the size of the tumours was found to influence the degree of systemic, but not tumour-specific, oscillations. The degree of vessel maturation was related to the amplitude of tumour-specific, but not systemic, oscillations. CONCLUSIONS: Our results provide further insights into the complexity of spontaneous fluctuations in tumour oxygenation and its relationship with tumour pathophysiology. These observations could be used to develop improved drug delivery strategies.
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Neoplasias/metabolismo , Neoplasias/patología , Oxígeno/metabolismo , Animales , Línea Celular Tumoral , Femenino , Hemoglobinas/metabolismo , Humanos , Hipoxia/metabolismo , Hipoxia/patología , Imagen por Resonancia Magnética/métodos , Ratones , Ratones DesnudosRESUMEN
BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted.
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Antineoplásicos/farmacología , Benzodiazepinonas/farmacología , Enfermedades de los Perros/tratamiento farmacológico , Pirroles/farmacología , Animales , Línea Celular Tumoral , Reactivos de Enlaces Cruzados/farmacología , ADN , Perros , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Citometría de Flujo , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ultrasound-mediated drug delivery is a promising means of enhancing delivery, distribution and effectiveness of drugs within tumours. In this review, prospects for exploiting ultrasound to improve the tumour delivery and distribution of radiolabelled antibodies for radioimmunotherapy and to overcome barriers imposed by tumour microenvironment are discussed.
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Terapia Molecular Dirigida/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Radioinmunoterapia/métodos , Animales , Anticuerpos/uso terapéutico , Humanos , UltrasonografíaRESUMEN
Nuclear imaging in conjunction with radioactive tracers enables noninvasive measurements of biochemical events in vivo. However, access to tracers remains limited due to the lack of methods for rapid assembly of radiolabeled molecules with the prerequisite biological activity. Herein, we report a one-pot, three-component, copper(II)-mediated reaction of azides, alkynes, and [(125)I]iodide to yield 5-[(125)I]iodo-1,2,3-triazoles. Using a selection of azides and alkynes in a combinatorial approach, we have synthesized a library of structurally diverse (125)I-labeled triazoles functionalized with bioconjugation groups, fluorescent dyes, and biomolecules. Our preliminary biological evaluation suggests that 5-[(125)I]iodo-1,2,3-triazoles are resistant to deiodination in vivo, both as small molecular probes and as antibody conjugates. The ability to incorporate radioactive iodide into triazoles directly from the parent azides and alkynes makes the method broadly applicable and offers the potential to rapidly assemble molecular probes from an array of structurally diverse, and readily available, building blocks.
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Radioisótopos de Yodo/química , Sondas Moleculares/química , Triazoles/química , Sondas Moleculares/síntesis química , Estructura Molecular , Radioquímica , Factores de Tiempo , Triazoles/síntesis químicaRESUMEN
We previously identified regulator of G-protein signaling 5 (RGS5) among several genes expressed by tumor-derived endothelial cells (EC). In this study, we provide the first in vivo/ex vivo evidence of RGS5 protein in the vasculature of ovarian carcinoma clinical specimens and its absence in human ovaries. Consistent with this, we show higher amounts of Rgs5 transcript in EC isolated from human cancers (as opposed to normal tissues) and demonstrate that expression is sustained by a milieu of factors typical of the proangiogenic tumor environment, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). Supporting these findings, we show elevated levels of Rgs5 mRNA in the stroma from strongly (as opposed to weakly) angiogenic ovarian carcinoma xenografts and accordingly, we also show more of the protein associated to the abnormal vasculature. RGS5 protein predominantly colocalizes with the endothelium expressing platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) and to a much lesser extent with perivascular/mural cells expressing platelet-derived growth factor receptor-beta (PDGFR-ß) or alpha smooth muscle actin (αSMA). To toughen the relevance of the findings, we demonstrate RGS5 in the blood vessels of other cancer models endowed with a proangiogenic environment, such as human melanoma and renal carcinoma xenografts; to the contrary, it was undetectable in the vasculature of normal mouse tissues. RGS5 expression by the cancer vasculature triggered and retained by the proangiogenic microenvironment supports its exploitation as a novel biomarker and opens the path to explore new possibilities of therapeutic intervention aimed at targeting tumor blood vessels.
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Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Neovascularización Patológica , Proteínas RGS/metabolismo , Animales , Células Cultivadas , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias/genética , Neoplasias/patología , Pronóstico , Proteínas RGS/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The potential of radioimmunotherapy to selectively kill tumour cells is well established. However, optimisation is required with regards to increasing tumour localisation of antibodies. We used the PDGF-receptor inhibitor imatinib mesylate to improve tumour-specific antibody localisation in two models of colorectal adenocarcinoma and correlated antibody localisation with changes to tumour microvasculature. Mice bearing human colorectal xenografts (LS174T or SW1222) were treated with imatinib prior to administration of radiolabeled anti-CEA antibodies ((125)I-A5B7). Whole tumour and regional localisation of radiolabeled antibodies were measured. Microvessel density and pericyte coverage were quantified in whole tumours and correlated with (125)I-A5B7 localisation. Imatinib increased uptake of (125)I-A5B7 in LS174T but not SW1222 tumours after 48 h (p < 0.05). Imatinib reduced microvessel density in both models (p < 0.05) but reduced pericyte attachment to endothelial cells only in SW1222 xenografts (p < 0.05). Imatinib increases antibody distribution in LS174T tumours but not SW1222 tumours, and this correlated to changes in tumour microvessels. Accelerated clearance of radiolabeled antibody from normal tissues in both models resulted in enhanced tumour to normal tissue ratios. This improvement in tumour/normal tissue ratio has potential clinical benefit from a therapy and imaging perspective, and merits further investigation.
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Adenocarcinoma/terapia , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/terapia , Modelos Animales de Enfermedad , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Radioinmunoterapia , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Adenocarcinoma/inmunología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Anticuerpos Monoclonales/farmacocinética , Antineoplásicos/uso terapéutico , Benzamidas , Antígeno Carcinoembrionario/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Terapia Combinada , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Mesilato de Imatinib , Técnicas para Inmunoenzimas , Ratones , Ratones Desnudos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Distribución Tisular , Trasplante HeterólogoRESUMEN
The mTOR (mammalian target of rapamycin) promotes growth in response to nutrients and growth factors and is deregulated in numerous pathologies, including cancer. The mechanisms by which mTOR senses and regulates energy metabolism and cell growth are relatively well understood, whereas the molecular events underlining how it mediates survival and proliferation remain to be elucidated. Here, we describe the existence of the mTOR splicing isoform, TOR beta, which, in contrast to the full-length protein (mTOR alpha), has the potential to regulate the G(1) phase of the cell cycle and to stimulate cell proliferation. mTOR beta is an active protein kinase that mediates downstream signaling through complexing with Rictor and Raptor proteins. Remarkably, overexpression of mTOR beta transforms immortal cells and is tumorigenic in nude mice and therefore could be a proto-oncogene.
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Proliferación Celular , Transformación Celular Neoplásica , Proteínas Quinasas/metabolismo , Empalme del ARN , Animales , Ciclo Celular , Línea Celular , Humanos , Ratones , Ratones Desnudos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Quinasas/genética , Transporte de Proteínas , Proto-Oncogenes Mas , Serina-Treonina Quinasas TORRESUMEN
PURPOSE: Most radioimmunotherapy studies on radiolabeled antibody distribution are based on autoradiographic and radioluminographic data, which provide a lack of detailed information due to low resolution. We used fluorescently labeled anti-carcinoembryonic antigen (CEA) antibody (A5B7) to investigate quantitatively the kinetics and microdistribution of antibody in a clinically relevant orthotopic colorectal cancer model (LS174T) using high-resolution digital microscopy. EXPERIMENTAL DESIGN: Nude mice bearing LS174T liver orthotopic tumors received a single i.v. injection of fluorescently labeled A5B7 and were sacrificed at 10 minutes, 1 hour, or 24 hours postinjection. Before sacrifice, mice were injected with the perfusion marker Hoechst 33342. An anti-CD31 antibody was used to detect blood vessel distribution. Cryostat sections were processed with immunofluorescence procedures and analyzed with fluorescence microscopy and image analysis techniques. The fluorescence images were related to morphologic images of the same or adjacent tumor sections. RESULTS: Fluorescently labeled antibody showed rapid, selective uptake into tumor deposits, with a strong negative correlation with tumor size at 10 minutes and 1 hour (P < or = 0.01). By 24 hours, the correlation was no longer significant. The study showed movement of antibody across the tumor with time and a tendency to localize more uniformly by later time points (24 hours). The rate of antibody motility was similar in small and large tumor metastases, but small deposits showed more rapid antibody localization. Intratumoral vessels were positively related to tumor size (P < or = 0.001). CONCLUSION: The obtained data suggest that radioimmunotherapy can be highly efficient in an adjuvant or minimal residual disease setting.
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Anticuerpos Antineoplásicos/metabolismo , Antígeno Carcinoembrionario/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Hepáticas/secundario , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Antineoplásicos/inmunología , Vasos Sanguíneos/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Modelos Animales de Enfermedad , Colorantes Fluorescentes , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Ratones , Microscopía Fluorescente , Metástasis de la Neoplasia , RadioinmunoterapiaRESUMEN
PURPOSE: Photoacoustic imaging (PAI) is a novel noninvasive and nonionizing imaging technique that allows longitudinal imaging of tumor vasculature in vivo and monitoring of response to therapy, especially for vascular targeted chemotherapy agents. In this study, we used a novel high-resolution all-optical PAI scanner to observe the pharmacodynamic response to the vascular-disrupting agent OXi4503. EXPERIMENTAL DESIGN: Two models of colorectal carcinoma (SW1222 and LS174T) that possess differing pathophysiologic vascularization were established as subcutaneous tumors in mice. Monitoring of response was performed over a 16-day "regrowth" period following treatment at 40 mg/kg, and at day 2 for a "dose response" study at 40 mg/kg, 10 mg/kg, 1 mg/kg, and sham dose. RESULTS: Qualitative and quantitative changes in PA signal are observed, with an initial decrease followed by a plateau and subsequent return of signal indicating regrowth. Both tumor types exhibited a decrease in signal; however, the more vascularized SW1222 tumors show greater response to treatment. Decreasing the dose of OXi4503 led to a decrease in PA signal intensity of 60%, 52%, and 20% in SW1222 tumors and 30%, 26%, and 4% for LS174T tumors. CONCLUSIONS: We have shown for the first time that PAI can observe the pharmacodynamic response of tumor vasculature to drug treatment both longitudinally and at different dose levels. Assessment of differing response to treatment based on vascular pathophysiologic differences among patients has the potential to provide personalized drug therapy; we have demonstrated that PAI, which is clinically translatable, could be a powerful tool for this purpose.
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Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Difosfatos/farmacología , Imagen Molecular/métodos , Neovascularización Patológica/tratamiento farmacológico , Técnicas Fotoacústicas/métodos , Estilbenos/farmacología , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Femenino , Estudios Longitudinales , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neovascularización Patológica/diagnóstico por imagen , Neovascularización Patológica/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Induction of apoptosis is often necessary for successful cancer therapy, and the non-invasive monitoring of apoptosis post-therapy could assist in clinical decision making. Isatins are a class of compounds that target activated caspase-3 during apoptosis. Here we report the synthesis of the 5-iodo-1,2,3-triazole (FITI) analog of the PET tracer [18F]ICMT11 as a candidate tracer for imaging of apoptosis with SPECT, as well as PET. Labelling with radioiodine (123,125I) was achieved in 55 ± 12% radiochemical yield through a chelator-accelerated one-pot cycloaddition reaction mediated by copper(I) catalysis. The caspase-3 binding affinity and selectivity of FITI compares favourably to that of [18F]ICMT11 (Ki = 6.1 ± 0.9 nM and 12.4 ± 4.7 nM, respectively). In biodistribution studies, etoposide-induced cell death in a SW1222 xenograft model resulted in a 2-fold increase in tumour uptake of the tracer. However, the tumour uptake was too low to allow in vivo imaging of apoptosis with SPECT.
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Apoptosis/efectos de los fármacos , Caspasa 3/aislamiento & purificación , Radioisótopos de Yodo/farmacología , Neoplasias/diagnóstico por imagen , Animales , Apoptosis/genética , Caspasa 3/química , Caspasa 3/genética , Línea Celular Tumoral , Cobre/química , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacología , Xenoinjertos , Humanos , Radioisótopos de Yodo/química , Isatina/síntesis química , Isatina/farmacología , Ratones , Neoplasias/patología , Neoplasias/terapia , Radiofármacos/síntesis química , Radiofármacos/farmacología , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único/métodos , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
PURPOSE: The efficacy of solid tumor radioimmunotherapy is reduced by heterogeneous tumor distribution of the radionuclide, with dose mainly deposited in the normoxic region and by the relative radioresistance of hypoxic tumor cells. In an attempt to overcome these challenges, radioimmunotherapy was combined with 2-deoxy-d-glucose (2DG), a hypoxia-selective cytotoxic inhibitor of glucose metabolism. EXPERIMENTAL DESIGN: In vitro toxicity of 2DG in LS174T cultures was tested using a colony-forming assay. The effect of combining 2DG with radioimmunotherapy in vivo was tested by administering radiolabeled anti-carcinoembryonic antigen antibody ([(131)I]A5B7 IgG1 whole monoclonal) to nude mice bearing s.c. LS174T tumors, followed by 10 daily injections of 2DG (2.0 g/kg). Tumors were measured to assess therapeutic efficacy. RESULTS: Data from in vitro studies confirmed 2DG cytotoxicity in this cell line. Greater toxicity was observed under standard laboratory conditions and in hypoxic cultures than at intermediate, physiologically relevant levels of glucose and oxygen. Alone, 2DG had no effect on in vivo tumor growth (P = 0.377 compared with saline-treated controls). Combination of radioimmunotherapy with 2DG reduced the therapeutic effect of radioimmunotherapy (e.g., 150 microCi (131)I alone mean survival time, 48.33 +/- 16.83 days; combined with 2DG, 30.67 +/- 5.62 days, P = 0.038). CONCLUSIONS: The combination investigated had a detrimental effect on survival. It is suggested that a cellular metabolic response to more aggressive therapy, previously reported in vitro, caused this. The results of this study have implications for the clinical application of combined cancer therapies with an antimetabolic modality component.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Hipoxia de la Célula , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/radioterapia , Desoxiglucosa/uso terapéutico , Radioinmunoterapia/métodos , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Terapia Combinada/efectos adversos , Desoxiglucosa/efectos adversos , Femenino , Humanos , Ratones , Ratones Desnudos , Radioinmunoterapia/efectos adversos , Análisis de Supervivencia , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The combination of early diagnosis and complete surgical resection offers the greatest prospect of curative cancer treatment. An iodine-124/fluorescein-based dual-modality labeling reagent, 124I-Green, constitutes a generic tool for one-step installation of a positron emission tomography (PET) and a fluorescent reporter to any cancer-specific antibody. The resulting antibody conjugate would allow both cancer PET imaging and intraoperative fluorescence-guided surgery. 124I-Green was synthesized in excellent radiochemical yields of 92 ± 5% (n = 4) determined by HPLC with an improved one-pot three-component radioiodination reaction. The A5B7 carcinoembryonic antigen (CEA)-specific antibody was conjugated to 124I-Green. High tumor uptake of the dual-labeled A5B7 of 20.21 ± 2.70, 13.31 ± 0.73, and 10.64 ± 1.86%ID/g was observed in CEA-expressing SW1222 xenograft mouse model (n = 3) at 24, 48, and 72 h post intravenous injection, respectively. The xenografts were clearly visualized by both PET/CT and ex vivo fluorescence imaging. These encouraging results warrant the further translational development of 124I-Green for cancer PET imaging and fluorescence-guided surgery.
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Inmunoconjugados/química , Radioisótopos de Yodo/química , Neoplasias/diagnóstico por imagen , Neoplasias/cirugía , Animales , Anticuerpos Monoclonales/química , Xenoinjertos , Humanos , Ratones , Imagen Óptica , Tomografía de Emisión de Positrones/métodosRESUMEN
Proteasome inhibitors (PIs) are now standard of care for several cancers, and noninvasive biomarkers of treatment response are critically required for early patient stratification and treatment personalization. The present study evaluated whether chemical exchange (CEST) magnetic resonance imaging (MRI) can provide measurements that can be used as the noninvasive biomarkers of proteasome inhibition, alongside diffusion MRI and relaxometry. The sensitivity of human colorectal carcinoma cells to the PI Ixazomib was assessed via in vitro and in vivo dose-response experiments. Acute in vivo response to Ixazomib was assessed at three dosing concentrations, using CEST MRI (amide, amine, hydroxyl signals), diffusion MRI (ADC) and relaxometry (T1, T2). These responses were further evaluated with the known histological markers for Ixazomib and Bradford assay ex vivo. The CEST signal from amides and amines increased in proportion to Ixazomib dose in colorectal cancer xenografts. The cell lines differed in their sensitivity to Ixazomib, which was reflected in the MRI measurements. A mild stimulation in tumor growth was observed at low Ixazomib doses. Our results identify CEST MRI as a promising method for safely and noninvasively monitoring disrupted tumor protein homeostasis induced by proteasome inhibitor treatment, and for stratifying sensitivity between tumor types.
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Imagen por Resonancia Magnética , Inhibidores de Proteasoma/farmacología , Proteostasis/efectos de los fármacos , Amidas/análisis , Aminas/análisis , Animales , Apoptosis/efectos de los fármacos , Compuestos de Boro/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Imagen de Difusión por Resonancia Magnética , Relación Dosis-Respuesta a Droga , Femenino , Glicina/análogos & derivados , Glicina/farmacología , Humanos , Interpretación de Imagen Asistida por Computador , Ratones Desnudos , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Understanding the uptake of a drug by diseased tissue, and the drug's subsequent spatiotemporal distribution, are central factors in the development of effective targeted therapies. However, the interaction between the pathophysiology of diseased tissue and individual therapeutic agents can be complex, and can vary across tissue types and across subjects. Here, we show that the combination of mathematical modelling, high-resolution optical imaging of intact and optically cleared tumour tissue from animal models, and in vivo imaging of vascular perfusion predicts the heterogeneous uptake, by large tissue samples, of specific therapeutic agents, as well as their spatiotemporal distribution. In particular, by using murine models of colorectal cancer and glioma, we report and validate predictions of steady-state blood flow and intravascular and interstitial fluid pressure in tumours, of the spatially heterogeneous uptake of chelated gadolinium by tumours, and of the effect of a vascular disrupting agent on tumour vasculature.
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Antineoplásicos/metabolismo , Hidrodinámica , Modelos Teóricos , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiología , Línea Celular Tumoral , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Medios de Contraste/química , Medios de Contraste/metabolismo , Difosfatos/metabolismo , Difosfatos/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Gadolinio/química , Gadolinio/metabolismo , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Humanos , Procesamiento de Imagen Asistido por Computador , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Flujo Sanguíneo Regional , Estilbenos/metabolismo , Estilbenos/uso terapéutico , Trasplante HeterólogoRESUMEN
Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers.Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859-72. ©2018 AACR.
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Neoplasias Colorrectales/irrigación sanguínea , Líquido Extracelular/fisiología , Hidrodinámica , Imagen por Resonancia Magnética/métodos , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/patología , Sistemas de Liberación de Medicamentos , Humanos , Ratones , Ratones Desnudos , Modelos Biológicos , Neovascularización Patológica/patología , Fantasmas de ImagenRESUMEN
The magnetic properties and safety of dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) have facilitated their clinical use as MRI contrast agents and stimulated research on applications for SPIONs in particle imaging and magnetic hyperthermia. The wider clinical potential of SPIONs, however, has been limited by their rapid removal from circulation via the reticuloendothelial system (RES). We explored the possibility of extending SPION circulatory time using fucoidan, a seaweed-derived food supplement, to inhibit RES uptake. The effects of fucoidan on SPION biodistribution were evaluated using ferucarbotran, which in its pharmaceutical formulation (Resovist) targets the RES. Ferucarbotran was radiolabeled at the iron oxide core with technetium-99m (99mTc; t1/2 = 6 h) or zirconium-89 (89Zr; t1/2 = 3.3 days). Results obtained with 99mTc-ferucarbotran demonstrated that administration of fucoidan led to a 4-fold increase in the circulatory half-life (t1/2 slow) from 37.4 to 150 min (n = 4; P < 0.0001). To investigate whether a longer circulatory half-life could lead to concomitant increased tumor uptake, the effects of fucoidan were tested with 89Zr-ferucarbotran in mice bearing syngeneic subcutaneous (GL261) tumors. In this model, the longer circulatory half-life achieved with fucoidan was associated with a doubling in tumor SPION uptake (n = 5; P < 0.001). Fucoidan was also effective in significantly increasing the circulatory half-life of perimag-COOH, a commercially available SPION with a larger hydrodynamic size (130 nm) than ferucarbotran (65 nm). These findings indicate successful diversion of SPIONs away from the hepatic RES and show realistic potential for future clinical applications.
RESUMEN
Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[ lmn][3,8]phenanthroline-1,3,6,8(2 H,7 H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.