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Recently, several chemotherapeutic drugs have been repositioned in neurological diseases, based on common biological backgrounds and the inverse comorbidity between cancer and neurodegenerative diseases. Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide, 4-HPR) is a synthetic derivative of all-trans-retinoic acid initially proposed in anticancer therapy for its antitumor effects combined with limited toxicity. Subsequently, fenretinide has been proposed for other diseases, for which it was not intentionally designed for, due to its ability to influence different biological pathways, providing a broad spectrum of pharmacological effects. Here, we review the most relevant preclinical and clinical findings from fenretinide and discuss its therapeutic role towards cancer and neurological diseases, highlighting the hormetic behavior of this pleiotropic molecule.
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Antineoplásicos , Fenretinida , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Fenretinida/farmacología , Fenretinida/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Tretinoina/farmacologíaRESUMEN
At present, there is no vaccine or effective standard treatment for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (or coronavirus disease-19 (COVID-19)), which frequently leads to lethal pulmonary inflammatory responses. COVID-19 pathology is characterized by extreme inflammation and amplified immune response with activation of a cytokine storm. A subsequent progression to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can take place, which is often followed by death. The causes of these strong inflammatory responses in SARS-CoV-2 infection are still unknown. As uncontrolled pulmonary inflammation is likely the main cause of death in SARS-CoV-2 infection, anti-inflammatory therapeutic interventions are particularly important. Fenretinide N-(4-hydroxyphenyl) retinamide is a bioactive molecule characterized by poly-pharmacological properties and a low toxicity profile. Fenretinide is endowed with antitumor, anti-inflammatory, antiviral, and immunomodulating properties other than efficacy in obesity/diabetic pathologies. Its anti-inflammatory and antiviral activities, in particular, could likely have utility in multimodal therapies for the treatment of ALI/ARDS in COVID-19 patients. Moreover, fenretinide administration by pulmonary delivery systems could further increase its therapeutic value by carrying high drug concentrations to the lungs and triggering a rapid onset of activity. This is particularly important in SARS-CoV-2 infection, where only a narrow time window exists for therapeutic intervention.
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Antiinflamatorios/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Fenretinida/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Citocinas , Fenretinida/farmacología , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Pandemias , Neumonía Viral/patología , Neumonía Viral/virología , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/metabolismo , SARS-CoV-2 , Transducción de Señal/efectos de los fármacosRESUMEN
PURPOSE: We describe a novel class of antitumor amphiphilic amines (RCn) based on a tricyclic amine hydrophilic head and a hydrophobic linear alkyl tail of variable length. METHODS: We tested the lead compound, RC16, for cytotoxicity and mechanism of cell death in several cancer cell lines, anti tumor efficacy in mouse tumor models, and ability to encapsulate chemotherapy drugs. RESULTS: These compounds displayed strong cytotoxic activity against cell lines derived from both pediatric and adult cancers. The IC50 of the lead compound, RC16, for normal cells including human keratinocytes, human fibroblasts and human umbilical vein endothelial cells was tenfold higher than for tumor cells. RC16 exhibited significant antitumor effects in vivo using several human xenografts and a metastatic model of murine neuroblastoma by both intravenous and oral administration routes. The amphiphilic character of RC16 triggered a spontaneous molecular self-assembling in water with formation of micelles allowing complexation of Doxorubicin, Etoposide and Paclitaxel. These micelles significantly improved the in vitro antitumor activity of these drugs as the enhancement of their aqueous solubility also improved their biologic availability. CONCLUSIONS: RC16 and related amphiphilic amines may be useful as a novel cancer treatment.
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Aminas/administración & dosificación , Antineoplásicos/administración & dosificación , Tensoactivos/administración & dosificación , Aminas/química , Aminas/farmacocinética , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular , Doxorrubicina/administración & dosificación , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos , Interacciones Farmacológicas , Etopósido/administración & dosificación , Etopósido/química , Etopósido/farmacocinética , Femenino , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Ratones Desnudos , Micelas , Ácido N-Acetilneuramínico/química , Nanopartículas , Paclitaxel/administración & dosificación , Paclitaxel/química , Paclitaxel/farmacocinética , Tamaño de la Partícula , Solubilidad , Propiedades de Superficie , Tensoactivos/química , Tensoactivos/farmacocinéticaRESUMEN
The present study deals with the preparation of albumin nanocapsules containing fenretinide and their evaluation in experimental models of human non-small cell lung cancer. These nanocapsules showed enhanced antitumor activity with respect to free fenretinide due to the solubilization effect of albumin on the hydrophobic drug, known to improve bioavailability. The high expression of caveolin-1 on the A549 cell surface further enhanced the antitumor activity of the nanoencapsulated fenretinide. Caveolin-1 favored albumin uptake and improved the efficacy of the fenretinide-loaded albumin nanocapsules, especially in 3-D cultures where the densely packed 3-D structures impaired drug diffusibility and severely reduced the activity of the free drug. The efficacy of the fenretinide albumin nanocapsules was further confirmed in tumor xenograft models of A549 by the significant delay in tumor progression observed with respect to control after intravenous administration of the novel formulation. FROM THE CLINICAL EDITOR: This study describes the preparation of fenretinide containing albumin nanocapsules and their evaluation in experimental models of non-small cell lung cancer, showing enhanced antitumor activity compared to free fenretinide.
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Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Fenretinida/administración & dosificación , Nanocápsulas/administración & dosificación , Albúminas/administración & dosificación , Albúminas/química , Animales , Antineoplásicos/administración & dosificación , Disponibilidad Biológica , Línea Celular Tumoral , Humanos , Ratones , Nanocápsulas/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Novel polylactide (PLA) microspheres endowed with hydrophilic and bioadhesive surfaces as injectable formulations for the controlled release of fenretinide were prepared, using a novel technique based on the co-precipitation of PLA with gelatin, at the interface of a liquid dispersion formed by the addition of N-methylpyrrolidone containing PLA and dextrin (DX), towards an aqueous solution of gelatin (G). The resulting PLA-G-DX microspheres were compared with others prepared by the same technique using polylactide-co-glycolide (PLGA), with or without DX, and with or without phosphatidylcholine. Of the different systems, the PLA-G-DX microspheres had the best morphological, dimensional and functional characteristics. They had the highest drug loading, and their drug release was the most efficient over time without any burst effect. Their in vitro anti-tumoural activity was strongly enhanced with respect to the pure fenretinide. This paralleled the increased drug concentration inside the cells due to their marked bioadhesion to the tumour cell membranes as indicated by scanning electron microscope images.
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Antineoplásicos , Fenretinida , Microesferas , Neoplasias/tratamiento farmacológico , Animales , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Bovinos , Línea Celular Tumoral , Preparaciones de Acción Retardada , Fenretinida/química , Fenretinida/farmacología , Gelatina/química , Gelatina/farmacología , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Microscopía Electroquímica de Rastreo , Neoplasias/metabolismo , Neoplasias/patología , Tamaño de la Partícula , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacología , Poliésteres/química , Poliésteres/farmacologíaRESUMEN
Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90-100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA.
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Apoptosis , Fenretinida , Leucemia Promielocítica Aguda , Humanos , Fenretinida/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/patología , Leucemia Promielocítica Aguda/metabolismo , Células HL-60 , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Nanopartículas/química , Supervivencia Celular/efectos de los fármacos , Micelas , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise and highly accurate for the measurement of the drug and the main metabolites. The lower limit of quantification resulted in 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate, respectively, was appropriate for the analysis, as demonstrated by the accuracy of between 96.8% and 102.4% for plasma and 96.6 to 102.3% for the tumor. The interdays precision and accuracy determined on quality controls at three different levels were in the ranges of 6.9 to 7.5% and 99.3 to 101.0%, and 0.96 to 1.91% and 102.3 to 105.8% for plasma and tumor, respectively. With the application of the novel assay in explorative pharmacokinetic studies, following acute and chronic oral administration of the nanoformulation, fenretinide was detected in plasma and tumor tissue at a concentration higher than the IC50 value necessary for in vitro inhibitory activity (i.e., 1-5 µM) in different cancer cells lines. We were also able to detect the presence in plasma and tumor of active and inactive metabolites of fenretinide.
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Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is also expressed in neurons, skin melanocytes, and peripheral nerve fibers. Immunotherapy with monoclonal anti-GD2 antibodies has a proven efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. However, the strong neuro-toxicity associated with anti-GD2 antibodies administration has hindered, until now, the possibility for dose-escalation and protracted use, thus restraining their therapeutic potential. Strategies to increase the efficacy of anti-GD2 antibodies are actively sought, with the aim to enable chronic treatments that could eradicate minimal residual disease and subsequent relapses, often occurring after treatment. Here, we report that Nanofenretinide and Nanospermidine improved the expression of GD2 in neuroblastoma cells (CHP-134) and provided different effects in combination with the anti-GD2 antibody naxitamab. In particular, Nanofenretinide significantly increased the cytotoxic effect of naxitamab while Nanospermidine inhibited cell motility at extents proportional to naxitamab concentration. In neuroblastoma cells characterized by a low and heterogeneous basal expression of GD2, such as SH-SY5Y, which may represent the cell heterogeneity in tumors after chemotherapy, both Nanofenretinide and Nanospermidine increased GD2 expression in approximately 50% of cells, thus shifting the tumor population towards improved sensitivity to anti-GD2 antibodies.
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This study reports on the preparation and evaluation of amphiphilic macromolecules based on branched polyethylene glycol covalently linked with alkyl hydrocarbon chains. These macromolecules easily dissolved in an aqueous environment, with formation of micellar nanoaggregates endowed with hydrophobic inner cores capable of hosting fenretinide by complexation. The complexes increased fenretinide aqueous solubility, while hindering its release as a free drug in an aqueous environment. Particle size analysis indicated dimensional suitability of the complexes for intravenous administration. Neuroblastoma cell lines (SH-SY5Y and NGP) exhibited increased sensitivity to fenretinide in complex as compared to free drug, associated with higher intracellular concentrations of fenretinide observed after treatment with the complex. Transmission electronic microscopy images revealed endocytosis of the micellar complex. Moreover, fenretinide conversion to its metabolite 4-oxo-fenretinide was delayed in cells treated with the complex, further supporting the hypothesis that fenretinide may be absorbed by micellar transport and exposed to the cytoplasm for conversion to its metabolite only after micelle destabilization.
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Fenretinida/administración & dosificación , Fenretinida/química , Nanocápsulas/química , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/fisiopatología , Polietilenglicoles/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalización/métodos , Diseño de Fármacos , Humanos , Micelas , Neuroblastoma/patologíaRESUMEN
A new strategy to cause cell death in tumors might be the increase of intracellular polyamines at concentrations above their physiological values to trigger the production of oxidation metabolites at levels exceeding cell tolerance. To test this hypothesis, we prepared nanospermidine as a carrier for spermidine penetration into the cells, able to escape the polyamine transport system that strictly regulates intracellular polyamine levels. Nanospermidine was prepared by spermidine encapsulation in nanomicelles and was characterized by size, zeta potential, loading, dimensional stability to dilution, and stability to spermidine leakage. Antitumor activity, ROS production, and cell penetration ability were evaluated in vitro in two neuroblastoma cell lines (NLF and BR6). Nanospermidine was tested as a single agent and in combination with nanofenretinide. Free spermidine was also tested as a comparison. The results indicated that the nanomicelles successfully transported spermidine into the cells inducing cell death in a concentration range (150-200 µM) tenfold lower than that required to provide similar cytotoxicity with free spermidine (1500-2000 µM). Nanofenretinide provided a cytostatic effect in combination with the lowest nanospermidine concentrations evaluated and slightly improved nanospermidine cytotoxicity at the highest concentrations. These data suggest that nanospermidine has the potential to become a new approach in cancer treatment. At the cellular level, in fact, it exploits polyamine catabolism by means of biocompatible doses of spermidine and, in vivo settings, it can exploit the selective accumulation of nanomedicines at the tumor site. Nanofenretinide combination further improves its efficacy. Furthermore, the proven ability of spermidine to activate macrophages and lymphocytes suggests that nanospermidine could inhibit immunosuppression in the tumor environment.
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Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities. We analyzed the effects of FEN on mutant SOD1 (mSOD1) toxicity in motoneuronal (NSC34) and a muscle (C2C12) cell lines and evaluated the impacts of chronic administration of a new nanomicellar fenretinide formulation (NanoMFen) on ALS disease progression in the SOD1G93A mouse model. The results showed that FEN significantly prevents the toxicity of mSOD1 expression in NSC34 motor neuron; furthermore, FEN is able to partially overcome the toxic effect of mSOD1 on the myogenic program of C2C12 muscle cells. Administration of NanoMFen ameliorates the disease progression and increases median survival of mSOD1G93A ALS mice, even when given after disease onset; beneficial effects in ALS mice, however, is restricted to female sex. Our data support the therapeutic potential of FEN against ALS-associated SOD1G93A mutant protein toxicity and promote further studies to elucidate specific cellular targets of the drug in ALS. Furthermore, the sex-related efficacy of NanoMFen in mSOD1G93A ALS mice strengthens the importance, in the perspective of a precision medicine approach, of gender pharmacology in ALS research.
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Esclerosis Amiotrófica Lateral , Fenretinida , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Animales , Modelos Animales de Enfermedad , Femenino , Fenretinida/farmacología , Ratones , Ratones Transgénicos , Proteínas Mutantes , Superóxido Dismutasa/genética , Superóxido Dismutasa-1/genéticaRESUMEN
PURPOSE: In a previous study, we demonstrated that the combination of fenretinide with lenalidomide, administered by a novel nanomicellar formulation (FLM), provided a strong antitumor effect in a neuroblastoma TrkB-expressing tumor. In this study, we tested the nanomicellar combination in an MYCN amplified neuroblastoma xenograft to assess its efficacy in different tumor genotypes and evaluate the interactions of the nanomicelles with the tumor cells. EXPERIMENTAL DESIGN: FLM was administered to mice bearing human NLF xenografts to evaluate its efficacy in comparison with the nanomicelles containing fenretinide alone (FM). Confocal laser-scanning fluorescence microscopy images of the NLF cells treated with FLM and FM allowed us to estimate the nanomicelle ability to transport the encapsulated drugs inside the tumor cells. Flow cytometric analysis of the cells from treated tumors was performed to assess the effect of treatment on GD2 expression and NK cell infiltration. RESULTS: FLM and FM decreased the growth of NLF xenografts at comparable extents during the treatment period. Afterwards, FLM induced a progressive tumor regression without regrowth, while FM treatment was followed by regrowth within 15-20 days after the end of treatment. Both FLM and FM were able to penetrate the tumor cells transporting the encapsulated drugs. FLM transported higher amount of fenretinide inside the cells. Also, FLM treatment strongly increased GD2 expression in treated tumors and slightly decreased the NK infiltration compared to FM. CONCLUSION: FLM treatment induced a superior antitumor response than FM in NLF xenografts, presumably due to the combined effects of fenretinide cytotoxicity and lenalidomide antiangiogenic activity. The ability of FLM to penetrate tumor cells, transporting the encapsulated drugs, substantially improved the therapeutic efficiency of this system. Moreover, the enhancement of GD2 expression in FLM treated tumors offers the possibility to further increase the antitumor effect by the use of anti-GD2 CAR-T cells and anti-GD2 antibodies in combination with FLM in multimodal therapies.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/tratamiento farmacológico , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Femenino , Fenretinida/administración & dosificación , Fenretinida/química , Regulación Neoplásica de la Expresión Génica , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/patología , Lenalidomida/administración & dosificación , Lenalidomida/química , Ratones Desnudos , Micelas , Microscopía Confocal , Nanoestructuras/química , Neuroblastoma/genética , Neuroblastoma/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: This study investigated the antitumor effect of a new nanomicellar complex obtained by combining the antitumor agent fenretinide with a quaternary amphiphilic amine RC16+ also endowed with antitumor activity. METHODS: The complex (Fen-RC16+) strongly improved the aqueous solubility of fenretinide (from 1,71 ± 0.08 µg/ml, pure fenretinide to 1500 ± 164 µg /ml, Fen-RC16+ complex) and provided a cytotoxic effect on SH-SY5Y neuroblastoma cell lines resulting from the intrinsic activity of both the complex components. Moreover, the mean size of the nanomicellar complex (ranging from 20 ± 1.97 nm to 40 ± 3.05 nm) was suitable for accumulation to the tumor site by the enhanced permeability and retention effect and the positive charge provided by the quaternary RC16+ induced adsorption of the complex on the tumor cell surface improving the intracellular concentration of fenretinide. RESULTS: All these characteristics made the Fen-RC16+ complex a multitasking system for antitumor therapy. CONCLUSION: Indeed its in vivo activity, evaluated on SH-SY5Y xenografts, was strong, and the tumor growth did not resume after the treatment withdrawal.
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Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , Fenretinida/administración & dosificación , Nanoestructuras/administración & dosificación , Compuestos de Amonio Cuaternario/administración & dosificación , Animales , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Femenino , Fenretinida/química , Humanos , Ratones Desnudos , Micelas , Neoplasias/tratamiento farmacológico , Compuestos de Amonio Cuaternario/químicaRESUMEN
PURPOSE: Currently >50% of high-risk neuroblastoma (NB) patients, despite intensive therapy and initial partial or complete response, develop recurrent NB due to the persistence of minimal residual disease (MRD) that is resistant to conventional antitumor drugs. Indeed, their low therapeutic index prevents drug-dose escalation and protracted administration schedules, as would be required for MRD treatment. Thus, more effective and less toxic therapies are urgently needed for the management of MRD. To address this aim, we evaluated a new combination of fenretinide and lenalidomide, both endowed with antitumor activity and low-toxicity profiles. New nanomicelles were prepared as carriers for this combination to maximize bioavailability and accumulation at the tumor site because of the enhanced permeability and retention (EPR) effect. EXPERIMENTAL DESIGN: New nanomicelles containing the fenretinide-lenalidomide combination (FLnMs) were prepared by a one-step method, providing high drug encapsulation and micelle dimensions suitable for tumor accumulation. Their administration to mice bearing human NB xenografts allowed us to evaluate their efficacy in comparison with the nanomicelles containing fenretinide alone (FnMs). RESULTS: Treatment by FLnMs significantly decreased the tumor growth of NB xenografts. FLnMs were more active than FnMs despite comparable fenretinide concentrations in tumors, and lenalidomide alone did not show cytotoxic activity in vitro against NB cells. The tumor mass at the end of treatment with FLnMs was predominantly necrotic, with a decreased Ki-67 proliferation index. CONCLUSION: FLnMs provided superior antitumor efficacy in NB xenografts compared to FnMs. The enhanced efficacy of the combination was likely due to the antiangiogenic effect of lenalidomide added to the cytotoxic effect of fenretinide. This new nanomicellar combination is characterized by a low-toxicity profile and offers a novel therapeutic option for the treatment of high-risk tumors where the persistence of MRD requires repeated administrations of therapeutic agents over long periods of time to avoid recurrent disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Fenretinida/farmacología , Lenalidomida/farmacología , Nanopartículas/química , Neuroblastoma/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estabilidad de Medicamentos , Femenino , Fenretinida/administración & dosificación , Humanos , Inyecciones Subcutáneas , Lenalidomida/administración & dosificación , Ratones , Ratones Desnudos , Micelas , Neuroblastoma/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. METHODS: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. RESULTS: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. CONCLUSION: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.
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Neoplasias del Colon/tratamiento farmacológico , Fenretinida/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Micelas , Células Madre Neoplásicas/efectos de los fármacos , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis , Disponibilidad Biológica , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Fenretinida/química , Fenretinida/farmacocinética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Melanoma/metabolismo , Melanoma/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Fenretinide is a synthetic retinoid characterized by anticancer activity in preclinical models and favorable toxicological profile, but also by a low bioavailability that hindered its clinical efficacy in former clinical trials. We developed a new formulation of fenretinide complexed with 2-hydroxypropyl-beta-cyclodextrin (nanofenretinide) characterized by an increased bioavailability and therapeutic efficacy. Nanofenretinide was active in cell lines derived from multiple solid tumors, in primary spheroid cultures and in xenografts of lung and colorectal cancer, where it inhibited tumor growth independently from the mutational status of tumor cells. A global profiling of pathways activated by nanofenretinide was performed by reverse-phase proteomic arrays and lipid analysis, revealing widespread repression of the mTOR pathway, activation of apoptotic, autophagic and DNA damage signals and massive production of dihydroceramide, a bioactive lipid with pleiotropic effects on several biological processes. In cells that survived nanofenretinide treatment there was a decrease of factors involved in cell cycle progression and an increase in the levels of p16 and phosphorylated p38 MAPK with consequent block in G0 and early G1. The capacity of nanofenretinide to induce cancer cell death and quiescence, together with its elevated bioavailability and broad antitumor activity indicate its potential use in cancer treatment and chemoprevention.
Asunto(s)
Antineoplásicos/uso terapéutico , Fenretinida/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Neuroblastoma (NB) is an extra-cranial solid tumour of childhood. In spite of the good clinical response to first-line therapy, complete eradication of NB cells is rarely achieved. Thus, new therapeutic strategies are needed to eradicate surviving NB cells and prevent relapse. Sodium ascorbate has been recently reported to induce apoptosis of B16 melanoma cells through down-regulation of the transferrin receptor, CD71. Since NB and melanoma share the same embryologic neuroectodermal origin, we used different human NB cell lines to assess whether the same findings occurred. RESULTS: We could observe dose- and time-dependent induction of apoptosis in all NB cell lines. Sodium ascorbate decreased the expression of CD71 and caused cell death within 24 h. An increase in the global and specific caspase activity took place, as well as an early loss of the mitochondrial transmembrane potential. Moreover, intracellular iron was significantly decreased after exposure to sodium ascorbate. Apoptotic markers were reverted when the cells were pretreated with the iron donor ferric ammonium citrate (FAC), further confirming that iron depletion is responsible for the ascorbate-induced cell death in NB cells. CONCLUSION: Sodium ascorbate is highly toxic to neuroblastoma cell lines and the specific mechanism of vitamin C-induced apoptosis is due to a perturbation of intracellular iron levels ensuing TfR-downregulation.
Asunto(s)
Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Ácido Ascórbico/farmacología , Hierro/metabolismo , Neuroblastoma/patología , Anexina A5/metabolismo , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neuroblastoma/metabolismo , Receptores de Transferrina/genética , Receptores de Transferrina/metabolismo , Azul de TripanoRESUMEN
PURPOSE: The major limitation to successful chemotherapy of neuroblastoma is the toxicity of traditional antitumor drugs. Hence, less toxic and more effective drugs are to be found, and novel formulations of conventional compounds allowing a more favorable biodistribution should be sought for. In an attempt to pursue this task, we recently synthesized an amphiphilic polymer based on a polyvinyl alcohol backbone [P10(4)]. EXPERIMENTAL DESIGN: The cytotoxic activity of P10(4) was evaluated both in vitro on neuroblastoma and melanoma cell lines and in vivo in pseudometastatic neuroblastoma models. Apoptosis was assessed by morphology, cytofluorimetric analysis of DNA content, and DNA fragmentation assay. Caspases activation was investigated by kits specific for caspase-1, caspase-2, caspase-3, caspase-4, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, and caspase-13. Colony formation was evaluated by soft agar assay. RESULTS: P10(4) exerted a potent cytotoxic activity on different neuroblastoma and melanoma cell lines through induction of both extrinsic and intrinsic caspase cascades and subsequent apoptosis. Moreover, the clonogenic potential of cells that survived P10(4) treatment was strongly reduced. Next, we tested the effects of P10(4) in nude mice injected with both a human and a murine neuroblastoma cell lines i.v. P10(4) significantly increased the life span and the long-term survival of treated mice over controls. No side effects were observed, even at doses higher than those used for therapeutic purposes. CONCLUSIONS: Our data suggest that P10(4) holds promise as an anticancer compound and, because of its lack of interaction with DNA, is unlikely to give rise to drug resistance.
Asunto(s)
Antineoplásicos/farmacología , Melanoma/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Polietilenglicoles/farmacología , Alcohol Polivinílico/análogos & derivados , Alcohol Polivinílico/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inyecciones Intravenosas , Ratones , Ratones Desnudos , Neuroblastoma/secundario , Polietilenglicoles/química , Alcohol Polivinílico/administración & dosificación , Alcohol Polivinílico/química , Relación Estructura-Actividad , Factores de Tiempo , Distribución Tisular , Trasplante Heterólogo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Articular cartilage is a highly organized tissue with complex biomechanical properties. However, injuries to the cartilage usually lead to numerous health concerns and often culminate in disabling symptoms, due to the poor intrinsic capacity of this tissue for self-healing. Although various approaches are proposed for the regeneration of cartilage, its repair still represents an enormous challenge for orthopedic surgeons. The field of tissue engineering currently offers some of the most promising strategies for cartilage restoration, in which assorted biomaterials and cell-based therapies are combined to develop new therapeutic regimens for tissue replacement. The current study describes the in vitro behavior of human adipose-derived mesenchymal stem cells (hADSCs) encapsulated within calcium/cobalt (Ca/Co) alginate beads. These novel chondrogenesis-promoting scaffolds take advantage of the synergy between the alginate matrix and Co(+2) ions, without employing costly growth factors (e.g., transforming growth factor betas (TGF-ßs) or bone morphogenetic proteins (BMPs)) to direct hADSC differentiation into cartilage-producing chondrocytes.
RESUMEN
The objective of this study was to evaluate the in vitro characteristics of polyvinylalcohol 10,000 (PVA10,000) and polyvinylalcohol 15,000 (PVA15,000) substituted with different alkyl chains (Iodododecane, Bromotetradecane) and crosslinked with Bis-chloro-ethoxy-ethane as an injectable drug carrier. beta-carotene was used as a lipophilic model drug. Physical mixtures of the drug and the spray-dried polymers were prepared and the release of the drug from the mixtures was evaluated in vitro at pH 7.4. The results indicated that the substituted PVA10,000 and PVA15,000 provided faster drug release with respect to the pure drug at pH 7.4. In particular, among the substituted PVA used, PVA10,000 and PVA15,000 substituted with Iodododecane and crosslinked with Bis-chloro-ethoxy-ethane improved drug release.