RESUMO
Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood-brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.
Assuntos
Encéfalo/metabolismo , Animais , Transporte Biológico/fisiologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Técnicas de Cocultura/métodos , Células Endoteliais/metabolismo , Humanos , Camundongos , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/metabolismo , Permeabilidade/efeitos dos fármacos , Tironinas/metabolismoRESUMO
Owing to their abilities to identify diseased conditions, to modulate biological processes, and to control cellular activities, magnetic nanoparticles have become one of the most popular nanomaterials in the biomedical field. Targeted drug delivery, controlled drug release, hyperthermia treatment, imaging, and stimulation of several biological entities are just some of the several tasks that can be accomplished by taking advantage of magnetic nanoparticles in tandem with magnetic fields. The huge interest towards this class of nanomaterials arises from the possibility to physically drive their spatiotemporal localization inside the body, and to deliver an externally applied stimulation at a target site. They in fact behave as actual nanotransducers, converting energy stemming from the external magnetic field into heat and mechanical forces, which act as signals for therapeutic processes such as hyperthermia and controlled drug release. Magnetic nanoparticles are a noninvasive tool that enables the remote activation of biological processes, besides behaving as formidable tracers for different imaging modalities, thus allowing to simultaneously carry out diagnosis and therapy. In view of all this, owing to their multifunctional and multitasking nature, magnetic nanoparticles are already one of the most important nanotechnological protagonists in medicine and biology, enabling an actual theranostic approach in many pathological conditions. In this Concept, we first provide a brief introduction on some physical properties of magnetic materials and on important features that determine the physical properties of magnetic nanoparticles. Thereafter, we will consider some major biomedical applications: hyperthermia, drug delivery/release, and nanoparticle-mediated control of biological processes, even at subcellular level.
Assuntos
Nanopartículas de Magnetita/química , Portadores de Fármacos/química , Humanos , Hipertermia Induzida , Campos Magnéticos , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Transdução de SinaisRESUMO
The lack of efficient targeting strategies poses significant limitations on the effectiveness of chemotherapeutic treatments. This issue also affects drug-loaded nanocarriers, reducing nanoparticles cancer cell uptake. We report on the fabrication and in vitro characterization of doxorubicin-loaded magnetic liposomes for localized treatment of liver malignancies. Colloidal stability, superparamagnetic behavior and efficient drug loading of our formulation were demonstrated. The application of an external magnetic field guaranteed enhanced nanocarriers cell uptake under cell medium flow in correspondence of a specific area, as we reported through in vitro investigation. A numerical model was used to validate experimental data of magnetic targeting, proving the possibility of accurately describing the targeting strategy and predict liposomes accumulation under different environmental conditions. Finally, in vitro studies on HepG2 cancer cells confirmed the cytotoxicity of drug-loaded magnetic liposomes, with cell viability reduction of about 50% and 80% after 24 h and 72 h of incubation, respectively. Conversely, plain nanocarriers showed no anti-proliferative effects, confirming the formulation safety. Overall, these results demonstrated significant targeting efficiency and anticancer activity of our nanocarriers and superparamagnetic nanoparticles entrapment could envision the theranostic potential of the formulation. The proposed magnetic targeting study could represent a valid tool for pre-clinical investigation regarding the effectiveness of magnetic drug targeting.
RESUMO
AIM: Glioblastoma multiforme is one of the deadliest forms of cancer, and current treatments are limited to palliative cares. The present study proposes a nanotechnology-based solution able to improve both drug efficacy and its delivery efficiency. MATERIALS & METHODS: Nutlin-3a and superparamagnetic nanoparticles were encapsulated in solid lipid nanoparticles, and the obtained nanovectors (nutlin-loaded magnetic solid lipid nanoparticle [Nut-Mag-SLNs]) were characterized by analyzing both their physicochemical properties and their effects on U-87 MG glioblastoma cells. RESULTS: Nut-Mag-SLNs showed good colloidal stability, the ability to cross an in vitro blood-brain barrier model, and a superior pro-apoptotic activity toward glioblastoma cells with respect to the free drug. CONCLUSION: Nut-Mag-SLNs represent a promising multifunctional nanoplatform for the treatment of glioblastoma multiforme.
Assuntos
Portadores de Fármacos/química , Glioblastoma/tratamento farmacológico , Imidazóis/química , Lipídeos/química , Nanopartículas de Magnetita/química , Piperazinas/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Transporte Biológico , Barreira Hematoencefálica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Humanos , Imidazóis/uso terapêutico , Cinética , Tamanho da Partícula , Piperazinas/uso terapêutico , Propriedades de SuperfícieRESUMO
The remote control of cellular functions through smart nanomaterials represents a biomanipulation approach with unprecedented potential applications in many fields of medicine, ranging from cancer therapy to tissue engineering. By actively responding to external stimuli, smart nanomaterials act as real nanotransducers able to mediate and/or convert different forms of energy into both physical and chemical cues, fostering specific cell behaviors. This report describes those classes of nanomaterials that have mostly paved the way to a "wireless" control of biological phenomena, focusing the discussion on some examples close to the clinical practice. In particular, magnetic fields, light irradiation, ultrasound, and pH will be presented as means to manipulate the cellular fate, due to the peculiar physical/chemical properties of some smart nanoparticles, thus providing realistic examples of "nanorobots" approaching the visionary ideas of Richard Feynman.
Assuntos
Nanomedicina/métodos , Nanopartículas/química , Nanoestruturas/química , Modelos Teóricos , OxirreduçãoRESUMO
Cerium oxide nanoparticles (nanoceria), well known for their pro- and antioxidant features, have been recently proposed for the treatment of several pathologies, including cancer and neurodegenerative diseases. However, interaction between nanoceria and biological molecules such as proteins and lipids, short blood circulation time, and the need of a targeted delivery to desired sites are some aspects that require strong attention for further progresses in the clinical application of these nanoparticles. The aim of this work is the encapsulation of nanoceria into a liposomal formulation in order to improve their therapeutic potentialities. After the preparation through a reverse-phase evaporation method, size, Z-potential, morphology, and loading efficiency of nanoceria-loaded liposomes were investigated. Finally, preliminary in vitro studies were performed to test cell uptake efficiency and preserved antioxidant activity. Nanoceria-loaded liposomes showed a good colloidal stability, an excellent biocompatibility, and strong antioxidant properties due to the unaltered activity of the entrapped nanoceria. With these results, the possibility of exploiting liposomes as carriers for cerium oxide nanoparticles is demonstrated here for the first time, thus opening exciting new opportunities for in vivo applications.
RESUMO
Sorafenib is an anticancer drug approved by the Food and Drug Administration for the treatment of hepatocellular and advanced renal carcinoma. The clinical application of sorafenib is promising, yet limited by its severe toxic side effects. The aim of this study is to develop sorafenib-loaded magnetic nanovectors able to enhance the drug delivery to the disease site with the help of a remote magnetic field, thus enabling cancer treatment while limiting negative effects on healthy tissues. Sorafenib and superparamagnetic iron oxide nanoparticles are encapsulated in solid lipid nanoparticles by a hot homogenization technique using cetyl palmitate as lipid matrix. The obtained nanoparticles (Sor-Mag-SLNs) have a sorafenib loading efficiency of about 90% and are found to be very stable in an aqueous environment. Plain Mag-SLNs exhibit good cytocompatibility, whereas an antiproliferative effect against tumor cells (human hepatocarcinoma HepG2) is observed for drug-loaded Sor-Mag-SLNs. The obtained results show that it is possible to prepare stable Sor-Mag-SLNs able to inhibit cancer cell proliferation through the sorafenib cytotoxic action, and to enhance/localize this effect in a desired area thanks to a magnetically driven accumulation of the drug. Moreover, the relaxivity properties observed in water suspensions hold promise for Sor-Mag-SLN tracking through clinical magnetic resonance imaging.
Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Lipídeos/química , Nanopartículas de Magnetita/química , Niacinamida/análogos & derivados , Compostos de Fenilureia/química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Dextranos/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Niacinamida/química , Niacinamida/toxicidade , Compostos de Fenilureia/toxicidade , SorafenibeRESUMO
Targeting the interaction of p53 with its natural inhibitor MDM2 by the use of small synthetic molecules has emerged as a promising pharmacological approach to restore p53 oncosuppressor function in cancers retaining wild-type p53. The first critical step in the experimental validation of newly synthesized small molecules developed to inhibit MDM2-p53 interaction is represented by the evaluation of their efficacy in preventing the formation of the MDM2-p53 complex. This can be achieved using the in vitro reconstructed recombinant MDM2-p53 complex in cell-free assays. A number of possible approaches have been proposed, which are however not suitable for screening large chemical libraries, due to the high costs of reagents and instrumentations, or the need of large amounts of highly pure recombinant proteins. Here we describe a rapid and cheap method for high-throughput screening of putative inhibitors of MDM2-p53 complex formation--based on the use of GST-recombinant proteins--that does not require antibodies and recombinant protein purification steps from bacterial cell lysates.