RESUMEN

Monocyte recruitment and transmigration are crucial in atherosclerotic plaque development. The multi-disease complexities aggravate the situation and continue to be a constant concern for understanding atherosclerosis plaque development. Herein, a 3D hydrogel-based model that integrates disease-induced microenvironments is sought to be designed, allowing us to explore the early stages of atherosclerosis, specifically examining monocyte fate in multi-disease complexities. As a proof-of-concept study, murine cells are employed to develop the model. The model is constructed with collagen embedded with murine aortic smooth muscle cells and a murine endothelial monolayer lining. The model achieves in vitro disease complexities using external stimuli such as glucose and lipopolysaccharide (LPS). Hyperglycemia exhibits a significant increase in monocyte adhesion but no enhancement in monocyte transmigration and foam cell conversion compared to euglycemia. Chronic infection achieved by LPS stimulation results in a remarkable augment in initial monocyte attachment and a significant increment in monocyte transmigration and foam cells in all concentrations. Moreover, the model exhibits synergistic sensitivity under multi-disease conditions such as hyperglycemia and infection, enhancing initial monocyte attachment, cell transmigration, and foam cell formation. Additionally, western blot data prove the enhanced levels of inflammatory biomarkers, indicating the model's capability to mimic disease-induced complexities during early atherosclerosis progression.

Asunto(s)

Aterosclerosis , Hiperglucemia , Placa Aterosclerótica , Animales , Ratones , Células Espumosas/metabolismo , Hidrogeles , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Aterosclerosis/metabolismo , Placa Aterosclerótica/metabolismo

RESUMEN

Currently, the treatment for acute disease encompasses the use of various biological drugs (BDs). However, the utilisation of BDs is limited due to their rapid clearance and non-specific accumulation in unwanted sites, resulting in a lack of therapeutic efficacy together with adverse effects. While nanoparticles are considered good candidates to resolve this problem, some available polymeric carriers for BDs were mainly designed for long-term sustained release. Thus, there is a need to explore new polymeric carriers for the acute disease phase that requires sustained release of BDs over a short period, for example for thrombolysis and infection. Poly(succinimide)-oleylamine (PSI-OA), a biocompatible polymer with a tuneable dissolution profile, represents a promising strategy for loading BDs for sustained release within a 48-h period. In this work, we developed a two-step nanoprecipitation method to load the model protein (e.g. bovine serum albumin and lipase) on PSI-OA. The characteristics of the nanoparticles were assessed based on various loading parameters, such as concentration, stirring rate, flow rate, volume ratio, dissolution and release of the protein. The optimised NPs displayed a size within 200 nm that is suitable for vasculature delivery to the target sites. These findings suggest that PSI-OA can be employed as a carrier for BDs for applications that require sustained release over a short period.

Asunto(s)

Aminas , Portadores de Fármacos , Nanopartículas , Humanos , Preparaciones de Acción Retardada , Enfermedad Aguda , Polímeros , Succinimidas , Tamaño de la Partícula

RESUMEN

Although poly(aspartic acid) (PASP), a strong calcium chelating agent, may be potentially effective in inhibition of vascular calcification, its direct administration may lead to side effects. In this study, we employed polysuccinimide, a precursor of PASP, to prepare targeted polysuccinimide-based nanoparticles (PSI NPs) that not only acted as a prodrug but also functioned as a carrier of additional therapeutics to provide powerful synergistic vascular anticalcification effect. This paper shows that chemically modified PSI-NPs can serve as effective nanocarriers for loading of hydrophobic drugs, in addition to anticalcification and antireactive oxygen species (anti-ROS) activities. Curcumin (Cur), with high loading efficiency, was encapsulated into the NPs. The NPs were stable for 16 h in physiological conditions and then slowly dissolved/hydrolyzed to release the therapeutic PASP and the encapsulated drug. The drug release profile was found to be in good agreement with the NP dissolution profile such that complete release occurred after 48 h at physiological conditions. However, under acidic conditions, the NPs were stable, and Cur cumulative release reached only 30% after 1 week. Though highly effective in the prevention of calcium deposition, PSI NPs could not prevent the osteogenic trans-differentiation of vascular smooth muscle cells (VSMCs). The presence of Cur addressed this problem. It not only further reduced ROS level in macrophages but also prevented osteogenic differentiation of VSMCs in vitro. The NPs were examined in vivo in a rat model of vascular calcification induced by kidney failure through an adenine diet. The inclusion of Cur and PSI NPs combined the therapeutic effects of both. Cur-loaded NPs significantly reduced calcium deposition in the aorta without adversely affecting bone integrity or noticeable side effects/toxicity as examined by organ histological and serum biochemistry analyses.

RESUMEN

Nanophotothermal therapy based on nanoparticles (NPs) that convert near-infrared (NIR) light to generate heat to selectively kill cancer cells has attracted immense interest due to its high efficacy and being free of ionizing radiation damage. Here, for the first time, we have designed a novel nanohybrid, silver-iron oxide NP (AgIONP), which was successfully tuned for strong absorbance at NIR wavelengths to be effective in photothermal treatment and dual-imaging strategy using MRI and photoacoustic imaging (PAI) in a cancer model in vivo and in vitro, respectively. We strategically combine the inherent anticancer activity of silver and photothermal therapy to render excellent therapeutic capability of AgIONPs. In vitro phantoms and in vivo imaging studies displayed preferential uptake of folate-targeted NPs in a cancer mice model, indicating the selective targeting efficiency of NPs. Importantly, a single intravenous injection of NPs in a cancer mice model resulted in significant tumor reduction, and photothermal laser resulted in a further substantial synergistic decrease in tumor size. Additionally, biosafety and biochemical assessment performed in mice displayed no significant difference between NP treatment and control groups. Overall, our folic acid AgIONPs displayed excellent potential in the simultaneous application for safe and successful targeted synergistic photothermal treatment and imaging of a cancer model.

Asunto(s)

Hierro , Plata , Animales , Ratones , Plata/farmacología , Diagnóstico por Imagen , Fantasmas de Imagen , Ácido Fólico

RESUMEN

Thrombosis and its complications are responsible for 30% of annual deaths. Limitations of methods for diagnosing and treating thrombosis highlight the need for improvements. Agents that provide simultaneous diagnostic and therapeutic activities (theranostics) are paramount for an accurate diagnosis and rapid treatment. In this study, silver-iron oxide nanoparticles (AgIONPs) are developed for highly efficient targeted photothermal therapy and imaging of thrombosis. Small iron oxide nanoparticles are employed as seeding agents for the generation of a new class of spiky silver nanoparticles with strong absorbance in the near-infrared range. The AgIONPs are biofunctionalized with binding ligands for targeting thrombi. Photoacoustic and fluorescence imaging demonstrate the highly specific binding of AgIONPs to the thrombus when functionalized with a single chain antibody targeting activated platelets. Photothermal thrombolysis in vivo shows an increase in the temperature of thrombi and a full restoration of blood flow for targeted group but not in the non-targeted group. Thrombolysis from targeted groups is significantly improved (p < 0.0001) in comparison to the standard thrombolytic used in the clinic. Assays show no apparent side effects of AgIONPs. Altogether, this work suggests that AgIONPs are potential theranostic agents for thrombosis.

Asunto(s)

Nanopartículas del Metal , Nanopartículas , Trombosis , Humanos , Terapia Fototérmica , Plata , Nanopartículas del Metal/uso terapéutico , Trombosis/diagnóstico por imagen , Trombosis/terapia , Imagen Multimodal/métodos , Nanopartículas Magnéticas de Óxido de Hierro , Nanomedicina Teranóstica/métodos , Fototerapia/métodos

RESUMEN

Nanoceria or cerium oxide nanoparticles characterised by the co-existing of Ce3+ and Ce4+ that allows self-regenerative, redox-responsive dual-catalytic activities, have attracted interest as an innovative approach to treating cancer. Depending on surface characteristics and immediate environment, nanoceria exerts either anti- or pro-oxidative effects which regulate reactive oxygen species (ROS) levels in biological systems. Nanoceria mimics ROS-related enzymes that protect normal cells at physiological pH from oxidative stress and induce ROS production in the slightly acidic tumour microenvironment to trigger cancer cell death. Nanoceria as nanozymes also generates molecular oxygen that relieves tumour hypoxia, leading to tumour cell sensitisation to improve therapeutic outcomes of photodynamic (PDT), photothermal (PTT) and radiation (RT), targeted and chemotherapies. Nanoceria has been engineered as a nanocarrier to improve drug delivery or in combination with other drugs to produce synergistic anti-cancer effects. Despite reported preclinical successes, there are still knowledge gaps arising from the inadequate number of studies reporting findings based on physiologically relevant disease models that accurately represent the complexities of cancer. This review discusses the dual-catalytic activities of nanoceria responding to pH and oxygen tension gradient in tumour microenvironment, highlights the recent nanoceria-based platforms reported to be feasible direct and indirect anti-cancer agents with protective effects on healthy tissues, and finally addresses the challenges in clinical translation of nanoceria based therapeutics.

Asunto(s)

Antineoplásicos , Cerio , Nanopartículas , Neoplasias , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Antioxidantes/metabolismo , Cerio/farmacología , Cerio/uso terapéutico , Nanopartículas/uso terapéutico , Nanopartículas/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Oxígeno/farmacología , Neoplasias/tratamiento farmacológico

RESUMEN

Stem cell (SC) therapies displayed encouraging efficacy and clinical outcome in various disorders. Despite this huge hype, clinical translation of SC therapy has been disheartening due to contradictory results from clinical trials. The ability to monitor migration and engraftment of cells in vivo represents an ideal strategy in cell therapy. Therefore, suitable imaging approach to track MSCs would allow understanding of migratory and homing efficiency, optimal route of delivery and engraftment of cells at targeted location. Hence, longitudinal tracking of SCs is crucial for the optimization of treatment parameters, leading to improved clinical outcome and translation. Magnetic resonance imaging (MRI) represents a suitable imaging modality to observe cells non-invasively and repeatedly. Tracking is achieved when cells are incubated prior to implantation with appropriate contrast agents (CA) or tracers which can then be detected in an MRI scan. This review explores and emphasizes the importance of monitoring the distribution and fate of SCs post-implantation using current contrast agents, such as positive CAs including paramagnetic metals (gadolinium), negative contrast agents such as superparamagnetic iron oxides and 19 F containing tracers, specifically for the in vivo tracking of MSCs using MRI. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Asunto(s)

Nanopartículas de Magnetita , Células Madre Mesenquimatosas , Rastreo Celular/métodos , Medios de Contraste , Imagen por Resonancia Magnética/métodos , Células Madre Mesenquimatosas/patología , Células Madre

RESUMEN

In this study, modular two-in-one nano-cocktails were synthesised to provide treatment of inflammatory diseases and also enable tracking of their delivery to the disease sites. Chitosan nano-cocktails loaded with treatment module (cerium oxide nanoparticles) and imaging module (iron oxide nanoparticles) were synthesised by electrostatic self-assembly (Chit-IOCO) and ionic gelation method (Chit-TPP-IOCO), respectively. Their MRI capability, anti-inflammatory and anti-fibrosis ability were investigated. Results demonstrated that Chit-IOCO significantly reduced the expression of TNF-α and COX-2, while Chit-TPP-IOCO reduced IL-6 in the LPS-stimulated macrophages RAW264.7. Cytotoxicity studies showed that the nano-cocktails inhibited the proliferation of macrophages. Additionally, Chit-IOCO exhibited higher in vitro MRI relaxivity than Chit-TPP-IOCO, indicating that Chit-IOCO is a better MRI contrast agent in macrophages. It was possible to track the delivery of Chit-IOCO to the inflamed livers of CCl4-treated C57BL/6 mice, demonstrated by a shortened T2⁎ relaxation time of the livers after injecting Chit-IOCO into mice. In vivo anti-inflammatory and blood tests demonstrated that Chit-IOCO reduced inflammation-related proteins (TNF-a, iNOS and Cox-2) and bilirubin in CCl4 treated C57BL/6. Histology images indicated that the nano-cocktails at the treatment doses did not affect the organs of the mice. Importantly, the nano-cocktail reduced fibrosis of CCl4-treated mouse liver. This is the first reported data on the anti-inflammation and anti-fibrosis efficacy of Chit-IOCO in C57BL/6 mouse liver inflammation model. Overall, Chit-IOCO nanoparticles have shown great potential in MR imaging/detecting and treating/therapeutic capabilities for inflammatory diseases.

Asunto(s)

Quitosano , Nanopartículas , Animales , Antiinflamatorios/farmacología , Compuestos Férricos , Ratones , Ratones Endogámicos C57BL

RESUMEN

Maintenance of a delicate haemostatic balance or a balance between clotting and bleeding is critical to human health. Irrespective of administration route, nanoparticles can reach the bloodstream and might interrupt the haemostatic balance by interfering with one or more components of the coagulation, anticoagulation, and fibrinolytic systems, which potentially lead to thrombosis or haemorrhage. However, inadequate understanding of their effects on the haemostatic balance, along with the fact that most studies mainly focus on the functionality of nanoparticles while forgetting or leaving behind their risk to the body's haemostatic balance, is a major concern. Hence, our review aims to provide a comprehensive depiction of nanoparticle-haemostatic balance interactions, which has not yet been covered. The synergistic roles of cells and plasma factors participating in haemostatic balance are presented. Possible interactions and interference of each type of nanoparticle with the haemostatic balance are comprehensively discussed, particularly focusing on the underlying mechanisms. Interactions of nanoparticles with innate immunity potentially linked to haemostasis are mentioned. Various physicochemical characteristics that influence the nanoparticle-haemostatic balance are detailed. Challenges and future directions are also proposed. This insight would be valuable for the establishment of nanoparticles that can either avoid unintended interference with the haemostatic balance or purposely downregulate/upregulate its key components in a controlled manner.

Asunto(s)

Hemostáticos , Nanopartículas , Trombosis , Hemorragia/inducido químicamente , Hemostasis , Hemostáticos/farmacología , Humanos

RESUMEN

Two important challenges in the field of 19F magnetic resonance imaging (MRI) are the maintenance of high fluorine content without compromising imaging performance, and effective targeting of small particles to diseased tissue. To address these challenges, we have developed a series of perfluoropolyether (PFPE)-based hyperbranched (HBPFPE) nanoparticles with attached peptide aptamer as targeting ligands for specific in vivo detection of breast cancer with high 19F MRI sensitivity. A detailed comparison of the HBPFPE nanoparticles (NPs) with the previously reported trifluoroethyl acrylate (TFEA)-based polymers demonstrates that the mobility of fluorinated segments of the HBPFPE nanoparticles is significantly enhanced (19F T2 > 80 ms vs 31 ms), resulting in superior MR imaging sensitivity. Selective targeting was confirmed by auto- and pair correlation analysis of fluorescence microscopy data, in vitro immunofluorescence, in vivo 19F MRI, ex vivo fluorescence and 19F NMR. The results highlight the high efficiency of aptamers for targeting and the excellent sensitivity of the PFPE moieties for 19F MRI. Of relevance to in vivo applications, the PFPE-based polymers exhibit much faster clearance from the body than the previously introduced perfluorocarbon emulsions ( t1/2 ∼ 20 h vs up to months). Moreover, the aptamer-conjugated NPs show significantly higher tumor-penetration, demonstrating the potential of these imaging agents for therapeutic applications. This report of the synthesis of polymeric aptamer-conjugated PFPE-based 19F MRI CAs with high fluorine content (∼10 wt %) demonstrates that these NPs are exciting candidates for detecting diseases with high imaging sensitivity.

Asunto(s)

Neoplasias de la Mama/diagnóstico por imagen , Éteres/química , Imagen por Resonancia Magnética con Fluor-19 , Fluorocarburos/química , Nanopartículas/química , Imagen Óptica , Animales , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos

RESUMEN

There is currently intense interest in new methods for understanding the fate of therapeutically-relevant cells, such as mesenchymal stem cells (MSCs). The absence of a confounding background signal and consequent unequivocal assignment makes 19F MRI one of the most attractive modalities for the tracking of injected cells in vivo. We describe here the synthesis of novel partly-fluorinated polymeric nanoparticles with small size and high fluorine content as MRI agents. The polymers, constructed from perfluoropolyether methacrylate (PFPEMA) and oligo(ethylene glycol) methacrylate (OEGMA) have favourable cell uptake profiles and excellent MRI performance. To facilitate cell studies the polymer was further conjugated with a fluorescent dye creating a dual-modal imaging agent. The efficacy of labelling of MSCs was assessed using 19F NMR, flow cytometry and confocal microscopy. The labelling efficiency of 2.6 ± 0.1 × 1012 19F atoms per cell, and viability of >90% demonstrates high uptake and good tolerance by the cells. This loading translates to a minimum 19F MRI detection sensitivity of ∼7.4 × 103 cells per voxel. Importantly, preliminary in vivo data demonstrate that labelled cells can be readily detected within a short acquisition scan period (12 minutes). Hence, these copolymers show outstanding potential for 19F MRI cellular tracking and for quantification of non-phagocytic and therapeutically-relevant cells in vivo.

Asunto(s)

Rastreo Celular , Medios de Contraste/química , Imagen por Resonancia Magnética con Fluor-19 , Células Madre Mesenquimatosas/citología , Animales , Femenino , Citometría de Flujo , Colorantes Fluorescentes , Flúor , Humanos , Ratones Endogámicos NOD , Ratones SCID , Microscopía Confocal

RESUMEN

The limited efficacy of cardiac cell-based therapy is thought to be due to poor cell retention within the myocardium. Hence, there is an urgent need for biomaterials that aid in long-term cell retention. This study describes the development of injectable microcapsules for the delivery of mesenchymal stem cells (MSCs) into the infarcted cardiac wall. These microcapsules comprise of low concentrations of agarose supplemented with extracellular matrix (ECM) proteins collagen and fibrin. Dextran sulfate, a negatively charged polycarbohydrate, was added to mimic glycosaminoglycans in the ECM. Cell viability assays showed that a combination of all components is necessary to support long-term survival and proliferation of MSCs within microcapsules. Following intramyocardial transplantation, microcapsules degraded slowly in vivo and did not induce a fibrotic foreign body response. Pre-labeling of encapsulated MSCs with iron oxide nanoparticles allowed continued cell-tracking by MRI over several weeks following transplantation into infarcted myocardium. In contrast, MSCs injected as cell suspension were only detectable for two days post transplantation by MRI. Histological analysis confirmed integration of transplanted cells at the infarct site. Therefore, microcapsules proved to be suitable for stem cell delivery into the infarcted myocardium and can overcome current limitations of poor cell retention in cardiac cell-based therapy.

Asunto(s)

Cápsulas , Proliferación Celular , Supervivencia Celular , Células Madre Mesenquimatosas/citología , Infarto del Miocardio/patología , Animales , Masculino , Ratas , Ratas Wistar

RESUMEN

Autologous cells hold great potential for personalized cell therapy, reducing immunological and risk of infections. However, low cell counts at harvest with subsequently long expansion times with associated cell function loss currently impede the advancement of autologous cell therapy approaches. Here, we aimed to source clinically relevant numbers of proangiogenic cells from an easy accessible cell source, namely peripheral blood. Using macromolecular crowding (MMC) as a biotechnological platform, we derived a novel cell type from peripheral blood that is generated within 5 days in large numbers (10-40 million cells per 100 ml of blood). This blood-derived angiogenic cell (BDAC) type is of monocytic origin, but exhibits pericyte markers PDGFR-ß and NG2 and demonstrates strong angiogenic activity, hitherto ascribed only to MSC-like pericytes. Our findings suggest that BDACs represent an alternative pericyte-like cell population of hematopoietic origin that is involved in promoting early stages of microvasculature formation. As a proof of principle of BDAC efficacy in an ischemic disease model, BDAC injection rescued affected tissues in a murine hind limb ischemia model by accelerating and enhancing revascularization. Derived from a renewable tissue that is easy to collect, BDACs overcome current short-comings of autologous cell therapy, in particular for tissue repair strategies.

Asunto(s)

Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Isquemia/terapia , Leucocitos Mononucleares/citología , Neovascularización Fisiológica , Pericitos/trasplante , Animales , Antígenos/genética , Antígenos/metabolismo , Biomarcadores/metabolismo , Adhesión Celular , Recuento de Células , Diferenciación Celular , Proliferación Celular , Expresión Génica , Miembro Posterior/irrigación sanguínea , Miembro Posterior/metabolismo , Miembro Posterior/patología , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Isquemia/metabolismo , Isquemia/patología , Leucocitos Mononucleares/fisiología , Macrófagos/citología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Desnudos , Pericitos/citología , Pericitos/fisiología , Cultivo Primario de Células , Proteoglicanos/genética , Proteoglicanos/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo

RESUMEN

The aim of the current study was to assess the ability of PET imaging agents to detect early response to therapy in an orthotopic experimental rodent model of glioma. Clinically, MRI and [(18)F]FDG PET are routinely used but their ability to assess early therapeutic response can be limited. In this study, nude rats were implanted with U87-MG tumors orthotopically and imaged with either [(18)F]FDG or [(18)F]FLT to determine which tracer acts as the most sensitive biomarker for evaluation of treatment response in animals undergoing anti-angiogenic therapy with sunitinib, a receptor tyrosine kinase (RTK) inhibitor. Of the radiopharmaceuticals tested, [(18)F]FLT proved to be the most sensitive biomarker in the proliferating glioma, based on tumour-to-normal tissue radiotracer uptake (TNR ~17) in comparison to [(18)F]FDG (TNR ~1.7). Furthermore, [(18)F]FLT displayed earlier assessment of therapy efficacy, than either tumour volume measured by MRI or [(18)F]FDG PET imaging. Overall, longitudinal molecular imaging with [(18)F]FLT provides earlier detection of therapy response than either of the commonly used clinical imaging modalities potentially improving patient management.

RESUMEN

UNLABELLED: Successful antiangiogenic therapies have been developed for the treatment of various cancers, but not all patients respond. Therefore, the early determination of therapy efficacy is essential for patient management. This study was done to evaluate the utility of various PET imaging biomarkers for early determination of the response to therapy with the antiangiogenic agent axitinib, a multiple receptor tyrosine kinase inhibitor, in tumors with diverse biologic characteristics. METHODS: Mice bearing U87-MG and MDA-MB-231 subcutaneous tumors were treated with axitinib (25 mg/kg intraperitoneally daily for 10 d), and tumor volumes were assessed with caliper measurements. The animals were concurrently imaged longitudinally with (18)F-FDG, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), and 2-(18)F-fluoroethyl-triazolyl conjugated c(RGDyK) peptide ((18)F-FtRGD) to determine the optimal radiopharmaceutical for measuring the early treatment response in the 2 tumor types. RESULTS: Daily administration of axitinib successfully retarded the growth of both U87-MG and MDA-MB-231 subcutaneous tumors, with significant differences in tumor volumes being observed from day 7 after therapy on. (18)F-FDG revealed a treatment efficacy response only at day 10 after treatment in both U87-MG tumor-bearing and MDA-MB-231 tumor-bearing animals. (18)F-FLT afforded earlier detection of the therapy response, revealing a significant difference between drug- and vehicle-treated animals at day 3 for animals bearing U87-MG tumors and at day 7 for animals bearing the more slowly growing MDA-MB-231 tumors. (18)F-FtRGD showed a rapid change in tumor retention that reached significance by day 7 in U87-MG tumor-bearing animals; in contrast, no significant difference in tumor retention was observed in MDA-MB-231 tumor-bearing animals. CONCLUSION: Longitudinal imaging with different radiopharmaceuticals displays various characteristics in different tumor types, depending on their biologic characteristics. Such studies may provide clinically important information to guide patient management and monitor the response to antiangiogenic therapy with the optimum noninvasive imaging agent in the relevant cancer type.

Asunto(s)

Didesoxinucleósidos , Fluorodesoxiglucosa F18 , Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Péptidos Cíclicos , Tomografía de Emisión de Positrones/métodos , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Axitinib , Línea Celular Tumoral , Femenino , Marcaje Isotópico , Ratones , Radiofármacos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del Tratamiento