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Despite their anti-inflammatory activity, corticosteroids are limited in clinic due to poor selectivity and their side effects. The ability to cross biological barriers makes them powerful yet unspecific, leading to toxicity and a low therapeutic index that limits their chronic use in autoimmune, inflammatory, and infectious diseases. It is needed another approachfor innovative targeted delivery strategies. This study aimed at investigating if the dexamethasone conjugation to Avidin-Nucleic-Acid-NanoASsembly (ANANAS) could allow its selective lung release in the bleomycin-induced pulmonary fibrosis model. Since recent evidence showed a selective ANANAS accumulation in macrophage lysosomes in a liver fibrosis model, an acid-sensitive hydrazone linker was used to facilitate dexamethasone release into pulmonary macrophages, key players in lung fibrosis. Systemic ANANAS-Dex administration in healthy mice showed no dexamethasone release in plasma or peripheral organs, with delivery exclusively targeting the liver, independent of the health status. While this confirmed the nanocarrier safety, it underscored the influence of the administration route, rather than the disease state, on ANANAS-Dex tropism. The study on intranasal administration highlighted that: 1) free Dex circulates in the bloodstream, while ANANAS keeps the drug confined in the lungs; 2) ANANAS-Dex results in sustained drug release in the lungs, enhancing the lungs/plasma-peripheral organs ratio; 3) fibrotic mice exhibited prolonged kinetics and macrophage targeting. Based on the biodistribution and pharmacokinetics studies, it is possible to achieve controlled and safe steroid release in lung disorders, reducing systemic toxicity and potentially enhancing clinical compliance.

The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led to the high overall survival of chronic myeloid leukemia (CML) patients. However, there are CML patients who show resistance to TKI therapy and are prone to progress to more advanced phases of the disease. So, implementing an alternative approach for targeting TKIs insensitive cells would be of the essence. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML cells are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activates the apoptotic pathway and leads to the reduction of amino acids and induction of huge metabolic stress in CML CD34+ cells. Altogether, our study shows that DHODH inhibition is a promising approach for targeting CML stem/progenitor cells and may help more patients discontinue the therapy.

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.

Fingolimod is a sphingosine 1-phosphate-receptor modulator approved for the oral treatment of relapsing–remitting multiple sclerosis (RRMS), a form of MS characterized by a pattern of exacerbation of neurological symptoms followed by recovery. Here, we validated a simple and rapid liquid chromatography–tandem mass spectrometry method for the measurement of the concentrations of Fingolimod and its active metabolite Fingolimod-Phosphate (Fingolimod-P) in human plasma. The lower limits of quantification were set at 0.3 and 1.5 ng/mL for Fingolimod and Fingolimod-P, respectively, and the linearity was in the range 0.3–150 ng Fingolimod/mL and 1.5–150 ng Fingolimod-P/mL. After protein precipitation, the extraction recoveries of both analytes were always above 60% with minimal matrix effect. The method was accurate and precise, satisfying the criteria set in the European Medicine Agency guidelines for bioanalytical method validation. The method was then applied to measure Fingolimod and Fingolimod-P concentrations in the plasma of 15 RRMS patients under chronic treatment with Fingolimod, administered daily at the dose of 0.5 mg for up to 24 months. No significant differences were observed between samples collected at 6, 12 and 24 months for both analytes, indicating that the drug’s bioavailability was unaffected by multiple daily doses up to 24 months. The levels of Fingolimod-P were about two-fold higher than the levels of the parent compound. The availability of this analytical method can allow the monitoring of the impact of plasma levels of the drug and its metabolite on inter-individual variability in clinical responses.

The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC.

The development of nanoparticles (NPs) to enable the passage of drugs across blood–brain barrier (BBB) represents one of the main challenges in neuropharmacology. In recent years, NPs that are able to transport drugs and interact with brain endothelial cells have been tested. Here, we investigated whether the functionalization of avidin-nucleic-acid-nanoassembly (ANANAS) with apolipoprotein E (ApoE) would allow BBB passage in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Our results demonstrated that ANANAS was able to transiently cross BBB to reach the central nervous system (CNS), and ApoE did not enhance this property. Next, we investigated if ANANAS could improve CNS drug delivery. To this aim, the steroid dexamethasone was covalently linked to ANANAS through an acid-reversible hydrazone bond. Our data showed that the steroid levels in CNS tissues of SOD1G93A mice treated with nanoformulation were below the detection limit. This result demonstrates that the passage of BBB is not sufficient to guarantee the release of the cargo in CNS and that a different strategy for drug tethering should be devised. The present study furthermore highlights that NPs can be useful in improving the passage through biological barriers but may limit the interaction of the therapeutic compound with the specific target.

Previous studies provided evidence for the alteration of brain cholesterol homeostasis in 129.Mecp2-null mice, an experimental model of Rett syndrome. The efficacy of statins in improving motor symptoms and prolonging survival of mutant mice suggested a potential role of statins in the therapy of Rett syndrome. In the present study, we show that Mecp2 deletion had no effect on brain and reduced serum cholesterol levels and lovastatin (1.5 mg/kg, twice weekly as in the previous study) had no effects on motor deficits and survival when Mecp2 deletion was expressed on a background strain (C57BL/6J; B6) differing from that used in the earlier study. These findings indicate that the effects of statins may be background specific and raise important issues to consider when contemplating clinical trials. The reduction of the brain cholesterol metabolite 24S-hydroxycholesterol (24S-OHC) found in B6.Mecp2-null mice suggests the occurrence of changes in brain cholesterol metabolism and the potential utility of using plasma levels of 24S-OHC as a biomarker of brain cholesterol homeostasis in RTT.

Aldehyde-oxidase-4 (AOX4) is one of the mouse aldehyde oxidase isoenzymes and its physiological function is unknown. The major source of AOX4 is the Harderian-gland, where the enzyme is characterized by daily rhythmic fluctuations. Deletion of the Aox4 gene causes perturbations in the expression of the circadian-rhythms gene pathway, as indicated by transcriptomic analysis. AOX4 inactivation alters the diurnal oscillations in the expression of master clock-genes. Similar effects are observed in other organs devoid of AOX4, such as white adipose tissue, liver and hypothalamus indicating a systemic action. While perturbations of clock-genes is sex-independent in the Harderian-gland and hypothalamus, sex influences this trait in liver and white-adipose-tissue which are characterized by the presence of AOX isoforms other than AOX4. In knock-out animals, perturbations in clock-gene expression are accompanied by reduced locomotor activity, resistance to diet induced obesity and to hepatic steatosis. All these effects are observed in female and male animals. Resistance to obesity is due to diminished fat accumulation resulting from increased energy dissipation, as white-adipocytes undergo trans-differentiation towards brown-adipocytes. Metabolomics and enzymatic data indicate that 5-hydroxyindolacetic acid and tryptophan are novel endogenous AOX4 substrates, potentially involved in AOX4 systemic actions.

3-Monochloropropane-1,2-diol (3-MCPD) is a chiral molecule naturally existing as a racemic mixture of (R)- and (S)-enantiomers. It was thoroughly investigated during the 1970s as a male antifertility drug until research was abandoned because of the side effects observed in toxicity studies. More than 20 years later, 3-MCPD, both in the free form and esterified to the fatty acids, was detected in vegetable oil and discovered to be a widespread contaminant in different processed foods. This review summarises the main toxicological studies on 3-MCPD and its esters. Current knowledge shows that the kidney and reproductive system are the primary targets of 3-MCPD toxicity, followed by neurological and immune systems. Despite uncertainties, in vivo studies suggest that renal and reproductive toxicity is mediated by toxic metabolites, leading to inhibition of glycolysis and energy depletion. Few acute, short-term, and subchronic toxicity studies have investigated the 3-MCPD esters. The pattern of toxicity was similar to that of free 3-MCPD. Some evidence suggests that the toxicity of 3-MCPD diesters may be milder than 3-MCPD, likely because of an incomplete enzymatic hydrolysis in the equivalent free form in the gastrointestinal tract. Further research to clarify absorption, metabolism, and long-term toxicity of 3-MCPD esters would be pivotal to improve the risk assessment of these compounds via food.