RESUMEN
Prostate cancer is the second most frequent malignancy in men worldwide and the fifth leading cause of death by cancer. Although most patients initially benefit from therapy, many of them will progress to metastatic castration-resistant prostate cancer, which still remains incurable. The significant mortality and morbidity rate associated with the progression of the disease results mainly from a lack of specific and sensitive prostate cancer screening systems, identification of the disease at mature stages, and failure of anticancer therapy. To overcome the limitations of conventional imaging and therapeutic strategies for prostate cancer, various types of nanoparticles have been designed and synthesized to selectively target prostate cancer cells without causing toxic side effects to healthy organs. The purpose of this review is to briefly discuss the selection criteria of suitable nanoparticles, ligands, radionuclides, and radiolabelling strategies for the development of nanoparticle-based radioconjugates for targeted imaging and therapy of prostate cancer and to evaluate progress in the field, focusing attention on their design, specificity, and potential for detection and/or therapy.
Asunto(s)
Nanopartículas , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Detección Precoz del Cáncer , Antígeno Prostático Específico , Radiofármacos/uso terapéutico , Nanopartículas/uso terapéuticoRESUMEN
Coralyne is a synthetic analog of berberine related to protoberberine-isoquinoline alkaloids. Isoquinoline derivatives and analogs are renowned as potent radiosensitizers with potential medical application. In the present study, we investigated the effect of coralyne on the cell death, cytoskeletal changes and cell cycle progression of irradiated A549 cells. A clonogenic assay revealed that coralyne pretreatment decreased the viability of A549 cells in a time- and dose-dependent manner. Moreover, exposure to coralyne and ionizing radiation (IR) markedly altered the filamentous actin cytoskeletal architecture and integrin-ß binding sites of A549 cells. Treatment with 1-25 µM coralyne in combination with 2 Gy of IR significantly reduced the percentage of cells in G2/M phase compared with 2 Gy IR alone. These results indicate that coralyne is a potent radiosensitizing agent that may find an application in medicine.
Asunto(s)
Alcaloides de Berberina/farmacología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Células A549 , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de la radiación , Humanos , Microscopía Confocal , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
Metastatic castration-resistant prostate cancer (mCRPC) is a progressive and incurable disease with poor prognosis for patients. Despite introduction of novel therapies, the mortality rate remains high. An attractive alternative for extension of the life of mCRPC patients is PSMA-based targeted radioimmunotherapy. In this paper, we extended our in vitro study of 223Ra-labeled and PSMA-targeted NaA nanozeolites [223RaA-silane-PEG-D2B] by undertaking comprehensive preclinical in vitro and in vivo research. The toxicity of the new compound was evaluated in LNCaP C4-2, DU-145, RWPE-1 and HPrEC prostate cells and in BALB/c mice. The tissue distribution of 133Ba- and 223Ra-labeled conjugates was studied at different time points after injection in BALB/c and LNCaP C4-2 tumor-bearing BALB/c Nude mice. No obvious symptoms of antibody-free and antibody-functionalized nanocarriers cytotoxicity and immunotoxicity was found, while exposure to 223Ra-labeled conjugates resulted in bone marrow fibrosis, decreased the number of WBC and platelets and elevated serum concentrations of ALT and AST enzymes. Biodistribution studies revealed high accumulation of 223Ra-labeled conjugates in the liver, lungs, spleen and bone tissue. Nontargeted and PSMA-targeted radioconjugates exhibited a similar, marginal uptake in tumour lesions. In conclusion, despite the fact that NaA nanozeolites are safe carriers, the intravenous administration of NaA nanozeolite-based radioconjugates is dubious due to its high accumulation in the lungs, liver, spleen and bones.
Asunto(s)
Inmunoconjugados/farmacocinética , Nanopartículas , Neoplasias de la Próstata/terapia , Radiofármacos/farmacocinética , Radio (Elemento) , Nanomedicina Teranóstica , Zeolitas , Animales , Anticuerpos Monoclonales , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Fenómenos Químicos , Técnicas de Química Sintética , Modelos Animales de Enfermedad , Diseño de Fármacos , Perfilación de la Expresión Génica , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Marcaje Isotópico , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Nanopartículas/química , Neoplasias de la Próstata/diagnóstico , Radiofármacos/administración & dosificación , Radiofármacos/efectos adversos , Radiofármacos/química , Radio (Elemento)/química , Distribución Tisular , Ensayos Antitumor por Modelo de Xenoinjerto , Zeolitas/químicaRESUMEN
Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. Due to the significant mortality and morbidity rate associated with the progression of this disease, there is an urgent need for new and targeted treatments. In this review, we summarize the recent advances in research on identification of prostate tissue-specific antigens for targeted therapy, generation of highly specific and selective molecules targeting these antigens, availability of therapeutic radionuclides for widespread medical applications, and recent achievements in the development of new-generation small-molecule inhibitors and antibody-based strategies for targeted prostate cancer therapy with alpha-, beta-, and Auger electron-emitting radionuclides.
Asunto(s)
Terapia Molecular Dirigida , Neoplasias de la Próstata/terapia , Radioisótopos , Radiofármacos , Animales , Biomarcadores de Tumor , Desarrollo de Medicamentos , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ligandos , Masculino , Terapia Molecular Dirigida/métodos , Nanopartículas/química , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Radioisótopos/administración & dosificación , Radiofármacos/administración & dosificación , Radiofármacos/química , Nanomedicina TeranósticaRESUMEN
Microglial cells clear the brain of pathogens and harmful debris, including amyloid-ß (Aß) deposits that are formed during Alzheimer's disease (AD). We studied the expression of Msr1, Ager and Cd36 receptors involved in Aß uptake and expression of Cd33 protein, which is considered a risk factor in AD. The effect of silver nanoparticles (AgNPs) and cadmium telluride quantum dots (CdTeQDs) on the expression of the above receptors and Aß uptake by microglial cells was investigated. Absorption of Aß and NPs was confirmed by confocal microscopy. AgNPs, but not CdTeQDs, caused a decrease in Aß accumulation. By using a specific inhibitor-polyinosinic acid-we demonstrated that Aß and AgNPs compete for scavenger receptors. Real-time PCR showed up-regulation of Cd33 and Cd36 gene expression after treatment with CdTeQDs for 24 h. Analysis of the abundance of the receptors on the cell surface revealed that AgNP treatment significantly reduced the presence of Msr1, Cd33, Ager and Cd36 receptors (6 and 24 h), whereas CdTeQDs increased the levels of Msr1 and Cd36 (24 h). To summarize, we showed that AgNP uptake competes with Aß uptake by microglial cells and consequently can impair the removal of the aggregates. In turn, CdTeQD treatment led to the accumulation of proinflammatory Cd36 protein on the cell surface.
RESUMEN
Prostate cancer is the second most frequent malignancy in men worldwide. Unfortunately, current therapies often lead to the onset of metastatic castration-resistant prostate cancer (mCRPC), causing significant mortality. Therefore, there is an urgent need for new and targeted therapies that are advantageous over the current ones. Recently, the PSMA-targeted radioligand therapy of mCRPC has shown very promising results. In line with this, we described the synthesis of a new radioimmunoconjugate, 223RaA-silane-PEG-D2B, for targeted mCRPC therapy. The new compound consists of a NaA zeolite nanocarrier loaded with the α-particle emitting Ra-223 radionuclide, functionalized with the anti-PSMA D2B antibody. Physicochemical properties of the synthesized compound were characterized by standard methods (HR-SEM, TEM, XRD, FTIR, EDS, NTA, DLS, BET, TGA). The targeting selectivity, the extent of internalization, and cytotoxicity were determined in LNCaP C4-2 (PSMA+) and DU-145 (PSMA-) cells. Our results supported the 223RaA-silane-PEG-D2B synthesis and revealed that the final product had a diameter ca. 120 nm and specific activity 0.65 MBq/1mg. The product was characterized by a high yield of stability (>95% up to 12 days). The conjugation reaction resulted in approximately 50 antibodies/nanoparticle. The obtained radioimmunoconjugate bound specifically and internalized into PSMA-expressing LNCaP C4-2 cells, but not into PSMA-negative DU-145 cells. 223RaA-silane-PEG-D2B demonstrated also potent cytotoxicity in LNCaP C4-2 cells. These promising results require further in vivo evaluation of 223RaA-silane-PEG-D2B with regard to its toxicity and therapeutic efficacy.