RESUMO
Background: Despite the improvement in clinical outcomes for head and neck squamous cell carcinoma (HNSCC) as the result of cetuximab, patients may present with or develop resistance that increases tumor recurrence rates and limits clinical efficacy. Therefore, identifying those patients who are or become resistant is essential to tailor the best therapeutic approach. Materials and Methods: Cetuximab was conjugated to p-NCS-Bz-DFO and labeled with 89Zr. The resistance model was developed by treating FaDu cells with cetuximab. Western blotting (WB) and specific binding assays were performed to evaluate epidermal growth factor receptor (EGFR) expression and 89Zr-DFO-cetuximab uptake in FaDu cetuximab-resistant (FCR) and FaDu cetuximab-sensitive (FCS) cells. Positron emission tomography imaging and biodistribution were conducted in NU/NU nude mice implanted with FCR or FCS cells. Results: Cetuximab was successfully radiolabeled with 89Zr (≥95%). Binding assays performed in FCR and FCS cells showed significantly lower 89Zr-DFO-cetuximab uptake in FCR (p < 0.0001). WB suggests that the resistance mechanism is associated with EGFR downregulation (p = 0.038). This result is in agreement with the low uptake of 89Zr-DFO-cetuximab in FCR cells. Tumor uptake of 89Zr-DFO-cetuximab in FCR was significantly lower than FCS tumors (p = 0.0340). Conclusions: In this work, the authors showed that 89Zr-DFO-cetuximab is suitable for identification of EGFR downregulation in vitro and in vivo. This radiopharmaceutical may be useful for monitoring resistance in HNSCC patients during cetuximab therapy.
Assuntos
Cetuximab/farmacologia , Desferroxamina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/patologia , Imagem Molecular/métodos , Radioisótopos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Zircônio/metabolismo , Animais , Apoptose , Proliferação de Células , Cetuximab/administração & dosagem , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Camundongos , Camundongos Nus , Compostos Radiofarmacêuticos/metabolismo , Sideróforos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Titanium and zirconium are biomaterials that present a layer of titanium dioxide (TiO(2)) or zirconium dioxide (ZrO(2)). As a result of corrosion, microparticles can be released into the bioenvironment, and their effect on tissues is seemingly associated with differences in the physicochemical properties of these metals. The aim of this study was to perform a long-term evaluation of the distribution, destination, and potential risk of TiO(2) and ZrO(2) microparticles that might result from the corrosion process. Wistar rats were i.p. injected with an equal dose of either TiO(2) or ZrO(2) suspension. The following end-points were evaluated at 3, 6, and 18 months: (a) the presence of particles in blood cells and liver and lung tissue, (b) Ti and Zr deposit quantitation, (c) oxidant-antioxidant balance in tissues, and (d) O(2)(-) generation in alveolar macrophages. Ti and Zr particles were detected in blood mononuclear cells and in organ parenchyma. At equal doses and times postadministration, Ti content in organs was consistently higher than Zr content. Ti elicited a significant increase in O(2)(-) generation in the lung compared to Zr. The consumption of antioxidant enzymes was greater in the Ti than in the Zr group. The present study shows that the biokinetics of TiO(2) and ZrO(2) depends on particle size, shape, and/or crystal structure.
Assuntos
Materiais Biocompatíveis/metabolismo , Titânio/metabolismo , Zircônio/metabolismo , Animais , Antioxidantes/metabolismo , Materiais Biocompatíveis/química , Biomarcadores/metabolismo , Corrosão , Macrófagos Alveolares/citologia , Macrófagos Alveolares/metabolismo , Masculino , Teste de Materiais , Oxirredução , Estresse Oxidativo , Tamanho da Partícula , Ratos , Ratos Wistar , Superóxidos/metabolismo , Propriedades de Superfície , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Distribuição Tecidual , Titânio/química , Zircônio/químicaRESUMO
Materials and devices intended for end-use applications as implants and medical devices must be evaluated to determine their biocompatibility potential in contact with physiological systems. The use of standard practices of biological testing provides a reasonable level of confidence concerning the response of a living organism to a given material or device, as well as guidance in selecting the proper procedures to be carried out for the screening of new or modified materials. This article presents results from cytotoxicity assays of cell culture, skin irritation, and acute toxicity by systemic and intracutaneous injections for powders, ceramic bodies, and extract liquids of hydroxyapatite (HA), calcia partially stabilized zirconia (ZO), and two types of zirconia-hydroxyapatite composites (Z4H6 and Z6H4) with potential for future use as orthopedic and dental implants. They indicate that these materials present potential for this type of application because they meet the requirements of the standard practices recommended for evaluating the biological reactivity of ATCC cell cultures (CCL1 NCTC clone 929 of mouse connective tissue and CCL 81 of monkey connective tissue) and animals (rabbit and mouse) with direct or indirect patient contact, or by the injection of specific extracts prepared from the material under test. In addition, studies involving short-term intramuscular and long-term implantation assays to estimate the reaction of living tissue to the composites studied, and investigations on long-term effects that these materials can cause on the cellular metabolism, are already in progress.