Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule

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

Pulmonary delivery of fenretinide: A possible adjuvant treatment in COVID-19

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

The radio/gamma-ray connection from 120 MHz to 230 GHz

Radio loud active galactic nuclei are composed of different spatial features, each one characterized by different spectral properties in the radio band. Among them, blazars are the most common class of sources detected at gamma-rays by Fermi, and their radio emission is dominated by the flat spectrum compact core. In this contribution, we explore the connection between emission at high energy revealed by Fermi and at radio frequencies. Taking as a reference the strong and very highly significant correlation found between gamma rays and cm-λ radio emission, we explore the different behaviours found as we change the energy range in gamma rays and in radio, therefore changing the physical parameters of the zones involved in the emitted radiation. We find that the correlation weakens when we consider (1) gamma rays of energy above 10 GeV (except for high synchrotron peaked blazars) or (2) low frequency radio data taken by the Murchison Widefield Array; on the other hand, the correlation strengthens when we consider mm-λ data taken by Atacama Large Millimeter Array (ALMA)

The connection between radio and high energy emission in black hole powered systems in the SKA era

Strong evidence exists for a highly significant correlation between the radio flux density and gamma-ray energy flux in blazars revealed by Fermi. However, there are central issues that need to be clarified in this field: what are the counterparts of the about 30% of gamma-ray sources that are as yet unidentified? Are they just blazars in disguise or they are something more exotic, possibly associated with dark matter? How would they fit in the radio-gamma ray connection studied so far? With their superb sensitivity, SKA1-MID and SKA1-SUR will help to resolve all of these questions. Even more, while the radio-MeV/GeV connection has been firmly established, a radio-VHE connection has been entirely elusive so far. The advent of CTA in the next few years and the expected CTA-SKA1 synergy will offer the chance to explore this connection, even more intriguing as it involves the opposite ends of the electromagnetic spectrum and the acceleration of particles up to the highest energies. We are already preparing to address these questions by exploiting data from the various SKA pathfinders and precursors. We have obtained 18 cm European VLBI Network observations of E>10 GeV sources, with a detection rate of 83%. Moreover, we are cross correlating the Fermi catalogs with the MWA commissioning survey: when faint gamma-ray sources are considered, pure positional coincidence is not significant enough for selecting counterparts and we need an additional physical criterion to pinpoint the right object. It can be radio spectral index, variability, polarization, or compactness, needing high angular resolution in SKA1-MID; timing studies can also reveal pulsars, which are often found from dedicated searches of unidentified gamma-ray sources. SKA will be the ideal instrument for investigating these characteristics in conjunction with CTA. (abridged)Comment: 12 pages, to be published in the proceedings of "Advancing Astrophysics with the Square Kilometre Array", PoS(AASKA14)15

Gelatin crosslinked with dehydroascorbic acid as a novel scaffold for tissue regeneration with simultaneous antitumor activity

A porous scaffold was developed to support normal tissue regeneration in the presence of residual tumor disease. It was prepared by gelatin crosslinked with dehydroascorbic acid (DHA). A physicochemical characterization of the scaffold was carried out. SEM and mercury porosimetry revealed a high porosity and interconnection of pores in the scaffold. Enzymatic degradation provided 56% weight loss in ten days. The scaffold was also evaluated in vitro for its ability to support the growth of normal cells while hindering tumor cell development. For this purpose, primary human fibroblasts and osteosarcoma tumor cells (MG-63) were seeded on the scaffold. Fibroblasts attached the scaffold and proliferated, while the tumor cells, after an initial attachment and growth, failed to proliferate and progressively underwent cell death. This was attributed to the progressive release of DHA during the scaffold degradation and its cytotoxic activity towards tumor cells

A novel nanomicellar combination of fenretinide and lenalidomide shows marked antitumor activity in a neuroblastoma xenograft model

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\u2013lenalidomide 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

Nanomicellar Lenalidomide-Fenretinide Combination Suppresses Tumor Growth in an MYCN Amplified Neuroblastoma Tumor

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

Radio and gamma-ray follow-up of the exceptionally high activity state of PKS 1510-089 in 2011

We investigate the radio and gamma-ray variability of the flat spectrum radio quasar PKS 1510-089 in the time range between 2010 November and 2012 January. In this period the source showed an intense activity, with two major gamma-ray flares detected in 2011 July and October. During the latter episode both the gamma-ray and the radio flux density reached their historical peak. Multiwavelength analysis shows a rotation of about 380 deg of the optical polarization angle close in time with the rapid and strong gamma-ray flare in 2011 July. An enhancement of the optical emission and an increase of the fractional polarization both in the optical and in radio bands is observed about three weeks later, close in time with another gamma-ray outburst. On the other hand, after 2011 September a huge radio outburst has been detected, first in the millimeter regime followed with some time delay at centimeter down to decimeter wavelengths. This radio flare is characterized by a rising and a decaying stage, in agreement with the formation of a shock and its evolution, as a consequence of expansion and radiative cooling. If the gamma-ray flare observed in 2011 October is related to this radio outburst, then this strongly indicates that the region responsible for the gamma-ray variability is not within the broad line, but a few parsecs downstream along the jet.Comment: 14 pages, 12 figures, accepted for publication in MNRA

Radio spectra and polarisation properties of radio-loud Broad Absorption Line Quasars

We present multi-frequency observations of a sample of 15 radio-emitting Broad Absorption Line Quasars (BAL QSOs), covering a spectral range between 74 MHz and 43 GHz. They display mostly convex radio spectra which typically peak at about 1-5 GHz (in the observer's rest-frame), flatten at MHz frequencies, probably due to synchrotron self-absorption, and become steeper at high frequencies, i.e., >~ 20 GHz. VLA 22-GHz maps (HPBW ~ 80 mas) show unresolved or very compact sources, with linear projected sizes of <= 1 kpc. About 2/3 of the sample look unpolarised or weakly polarised at 8.4 GHz, frequency in which reasonable upper limits could be obtained for polarised intensity. Statistical comparisons have been made between the spectral index distributions of samples of BAL and non-BAL QSOs, both in the observed and the rest-frame, finding steeper spectra among non-BAL QSOs. However constraining this comparison to compact sources results in no significant differences between both distributions. This comparison is consistent with BAL QSOs not being oriented along a particular line of sight. In addition, our analysis of the spectral shape, variability and polarisation properties shows that radio BAL QSOs share several properties common to young radio sources like Compact Steep Spectrum (CSS) or Gigahertz-Peaked Spectrum (GPS) sources.Comment: 18 pages, 11 Postscript figures, 12 Tables. Accepted for publication in MNRA

A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells

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