Leptin-Activity Modulators and Their Potential Pharmaceutical Applications.

Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.

Bortezomib-Loaded Mesoporous Silica Nanoparticles Selectively Alter Metabolism and Induce Death in Multiple Myeloma Cells.

A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative (FR-) normal cells. FOL-MSN-BTZ efficacy studies were conducted by means of growth experiments, TEM, TUNEL assay and Western Blotting analysis (WB). Metabolic investigations were performed to assess cells metabolic response to MSNs treatments. FOL-MSN-BTZ exclusively killed FR+ MM cells, leading to an apoptotic rate that was comparable to that induced by free BTZ, and the effect was accompanied by metabolic dysfunction and oxidative stress. Importantly, FOL-MSN-BTZ treated FR- normal cells did not show any significant sign of injury or metabolic perturbation, while free BTZ was still highly toxic. Notably, the vehicle alone (MSN-FOL) did not affect any biological process in both tested cell models. These data show the striking specificity of FOL-MSN-BTZ toward FR+ tumor cells and the outstanding safety of the MSN-FOL vehicle, paving the way for a future exploitation of FOL-MSN-BTZ in MM target therapy.

Leptin Receptor as a Potential Target to Inhibit Human Testicular Seminoma Growth.

Although in past decades the adipokine leptin and its own receptor have been considered as significant cancer biomarkers, their potential involvement in human testicular seminoma growth and progression remains unexplored. Here, we showed that the expression of leptin and its receptor was significantly higher in human testicular seminoma compared with normal adult testis. Human seminoma cell line TCam-2 also expressed leptin along with the long and short isoforms of leptin receptor, and in response to leptin treatment showed enhanced activation of its downstream effectors. In line with these results, leptin stimulation significantly increased the proliferation and migration of TCam-2 cells. Treatment of TCam-2 cells with the peptide Leu-Asp-Phe-Ile (LDFI), a full leptin-receptor antagonist, completely reversed the leptin-mediated effects on cell growth and motility as well as reduced the expression of several leptin-induced target genes. More importantly, the in vivo xenograft experiments showed that LDFI treatment markedly decreased seminoma tumor growth. Interestingly, LDFI-treated tumors showed reduced levels of the proliferation marker Ki-67 as well as decreased expression of leptin-regulated genes. Taken together, these data identify, for the first time, leptin as a key factor able to affect testicular seminoma behavior, highlighting leptin receptor as a potential target for novel potential treatments in this type of cancer.

A titanium tetrachloride-based effective methodology for the synthesis of dipeptides.

A series of dipeptide systems have been easily achieved through a TiCl4-assisted condensation reaction. The reaction of N-protected amino acids with amino acid methyl esters in pyridine and in the presence of TiCl4 furnished the corresponding dipeptides with high yields and diastereoselectivity. The reaction was successfully applied to amino acids protected on the α-amino function with different protecting groups. The adopted experimental conditions allowed preserving both the protecting groups on the α-amino function and on the side chain functionalities. Furthermore, the preservation of the stereochemical integrity at the amino acid chiral centres has been verified.

Mesoporous silica-based hybrid materials for bone-specific drug delivery.

A mesoporous silica-based drug delivery device potentially useful for bone-specific drug delivery has been designed, developed and characterized starting from MSU-type mesoporous silica. The proposed system consists of a mesoporous silica nanoparticles (MSN) based vehicle, presenting alendronate as a targeting functionality for bone tissue while ibuprofen is used as a model molecule for the drugs to be delivered. The particles are functionalized on the external surface using a propionitrile derivative that is successively hydrolyzed to a carboxylic group. Alendronate, one of the most used member of the diphosphonate drug class, is electrostatically bonded to the external carboxyl functionalities of mesoporous silica. The obtained material has been characterized by powder X-ray diffraction, N2 adsorption-desorption porosimetry, UV-vis spectrophotometry, FT-IR spectrometry and MAS-NMR 13C and 29Si. Hydroxyapatite, which simulates the bone matrix, has been synthesized with the aim of testing the targeting activity of the obtained device. In a separate test, the MSNs have been loaded with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), and its release has been determined under neutral conditions by HPLC. Moreover, biological tests were carried out. The tested devices did not show any toxicity towards normal cells, confirming their high biocompatibility and the lack of off-target effects.

Dealing with Skin and Blood-Brain Barriers: The Unconventional Challenges of Mesoporous Silica Nanoparticles.

Advances in nanotechnology for drug delivery are fostering significant progress in medicine and diagnostics. The multidisciplinary nature of the nanotechnology field encouraged the development of innovative strategies and materials to treat a wide range of diseases in a highly specific way, which allows reducing the drug dosage and, consequently, improving the patient's compliance. Due to their good biocompatibility, easy synthesis, and high versatility, inorganic frameworks represent a valid tool to achieve this aim. In this context, Mesoporous Silica Nanoparticles (MSNs) are emerging in the biomedical field. For their ordered porosity and high functionalizable surface, achievable with an inexpensive synthesis process and being non-hazardous to biological tissues, MSNs offer ideal solutions to host, protect, and transport drugs to specific target sites. Extensive literature exists on the use of MSNs as targeted vehicles for systemic (chemo) therapy and for imaging/diagnostic purposes. However, the aim of this review is to give an overview of the last updates on the potential applications of the MSNs for Topical Drug Delivery (TDD) and as drug delivery systems into the brain, discussing their performances and advantages in dealing with these intriguing biological barriers.

Alternative formation of amides and ß-enaminones from aroyl chlorides using the TiCl4-trialkylamine reagent system.

The TiCl4/NR3 reagent system has been successfully employed for the synthesis of amides and ß-enaminones. The reaction of variously substituted benzoyl chlorides with the TiCl4/NR3 reagent system, by using two different experimental procedures (Method A and Method B), afforded alternatively the corresponding amides and ß-enaminones as unique or major products. The two developed protocols were investigated with a series of tertiary amines. The reactions, modulated by the presence of TiCl4, provided the corresponding amides or ß-enaminones with satisfactory yields. This paper reports a new method for carbon-carbon bond formation via the reaction of aroyl chlorides with the TiCl4/NR3 reagent system.

Formation of amides: one-pot condensation of carboxylic acids and amines mediated by TiCl4.

A general procedure for the synthesis of amides via the direct condensation of carboxylic acids and amines in the presence of TiCl4 is reported. The amidation reaction was performed in pyridine at 85 °C with a wide range of substrates providing the corresponding amide products in moderate to excellent yields and high purity. The reaction proceeds with low yields when both the carboxylic acid and the amine are sterically hindered. The process takes place with nearly complete preservation of the stereochemical integrity of chiral substrates.