A nanodelivered Vorinostat derivative is a promising oral compound for the treatment of visceral leishmaniasis.

There is currently no satisfactory treatment for visceral leishmaniasis; the disease is thus in desperate need of novel drugs. The ideal candidate should be effective, safe, affordable, and administered via the oral route. Histone deacetylases (HDACs) are involved in silencing critical regulatory pathways, including pro-apoptotic programs, and represent potential therapeutic targets for pharmacological interventions. O-alkyl hydroxamates have traditionally been considered to exert no effect on mammal HDACs. The aim of this study was to evaluate the effect of MDG, a SAHA derivative of the O-alkyl hydroxamate family with no activity on human histone deacetylase enzymes, on the visceral leishmaniasis causative agents and in a murine model of the disease. The effects of vorinostat, tubacin and valproic acid (well-known mammal HDAC inhibitors) on the parasite were also evaluated. MDG was found to be highly active against Leishmania infantum and L. donovani intracellular amastigotes in vitro but not against the promastigote stage. In contrast, vorinostat, tubacin and valproic acid showed no activity against the parasite. Assays investigating hERG and Cav1.2 channels in vitro found no evidence of MDG-driven cardiotoxicity. MDG showed neither hepatotoxicity nor mutagenicity, nor did it exert activity on cytochrome P450 enzymes. MDG was adsorbed onto gold nanoparticles for the in vivo experiments, performed on infected Balb/c mice. MDG was effective at reducing the parasite load in major target tissues (bone marrow, spleen and liver) in more than 70% at 25 mg/kg through both the oral and intraperitoneal route, proving more active than the reference compounds (meglumine antimoniate, MA) without showing toxicity. In addition, the combination of MDG and MA was very effective.

Topical Treatment of Leishmania tropica Infection Using (-)-α-Bisabolol Ointment in a Hamster Model: Effectiveness and Safety Assessment.

There is currently no reliable treatment for the management of cutaneous leishmaniasis, and intralesional antimonial injections remain the main treatment. The present work aims at evaluating the antileishmanial effectiveness and safety of (-)-α-bisabolol (1) in a novel topical formulation on a cutaneous leishmaniasis model involving Leishmania tropica-infected Syrian hamsters. The topical treatment with 1 reduced lesion thickness to 56% at 2.5%, showing a higher efficacy than the reference control, meglumine antimoniate. Other regimens (ointment at 1% and 5% and oral treatment at 200 mg/kg) reduced the footpad thickness as well. The skin parasite load decreased after the experiment in all treatment groups, particularly in those animals treated with the 2.5% formulation (83.2%). Treatment with (-)-α-bisabolol at different concentrations or through an oral route did not lead to the appearance of toxicity or side effects in healthy hamsters or infected animals. Therefore, topical (-)-α-bisabolol was more effective than meglumine antimoniate in this cutaneous leishmaniasis model without showing toxicity effects on the hamsters. These results are of great interest and might be used for the development of alternatives for the treatment of cutaneous leishmaniasis, either in monotherapy or in combination with other drugs whose skin permeability could be enhanced by this sesquiterpene.

Synergistic cytotoxicity of the poly (ADP-ribose) polymerase inhibitor ABT-888 and temozolomide in dual-drug targeted magnetic nanoparticles.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is associated with a poor prognosis because of a lack of effective treatment options. The objective of this study was to examine a new strategy for HCC treatment, namely the use of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor (ABT-888) together with Temozolomide (TMZ) incorporated onto magnetic nanoparticles. METHODS: Magnetic Fe3 O4 /Fe cores were encapsulated within a silica shell to facilitate the simultaneous incorporation of ABT-888 and TMZ. In vitro tests were performed with HepG2, Hep3B and PLC-PRF-5 liver tumoural cell lines and with WRL-68 liver non-tumoural cells. RESULTS: The magnetic nanocarriers were loaded simultaneously with ABT-888 and TMZ. High stability and extended release were achieved in culture medium. Confocal microscopy images showed that drug-loaded particles were uptaken and accumulated into the cytoplasm of liver tumoural cells, inducing the following effects: G2/M cell cycle arrest (P < 0.05), accumulation of DNA damage (P < 0.05), mitochondrial depolarization (P < 0.01), reduction in BCL-xL, FOS, JUND gene expression (P < 0.05), PARP-1 fragmentation, Caspase-3 activation and apoptotic cell death (P < 0.05). Interestingly, drugs loaded onto nanoparticles exhibited better efficiency than free drugs (cell death triggered by drug delivery nanosystem: 53.5% vs. 34.5% by free drugs, P = 0.01). CONCLUSIONS: These magnetic nanocompounds are able to incorporate both drugs simultaneously, enter the tumour cells and release them. ABT-888/TMZ/NPs decrease the transcription of key genes involved in tumour survival and induce apoptotic cell death in a more effective manner than is achieved by free drugs.

Effectiveness of an O-Alkyl Hydroxamate in Dogs with Naturally Acquired Canine Leishmaniosis: An Exploratory Clinical Trial.

Canine leishmaniosis is a challenge in veterinary medicine and no drug to date has achieved parasite clearance in dogs. Histone deacetylase inhibitors are a drug class widely used in cancer chemotherapy. We have successfully used O-alkyl hydroxamates (vorinostat derivatives) in the treatment of a laboratory model of visceral leishmaniasis without showing toxicity. In order to test the effectiveness of a particular compound, MTC-305, a parallel-group, randomized, single-centre, exploratory study was designed in naturally infected dogs. In this clinical trial, 18 dogs were allocated into 3 groups and were treated with either meglumine antimoniate (104 mg SbV/kg), MTC-305 (3.75 mg/kg) or a combination of both using a lower MTC-305 dose (1.5 mg/kg) through a subcutaneous route for 2 treatment courses of 30 days, separated by a 30-day rest period. After treatment, a follow-up time of 4 months was established. Parasite burden in bone marrow, lymph node and peripheral blood were quantified through qPCR. Antibody titres were determined through an immunofluorescence antibody test, and cytokine expression values were calculated through RT-qPCR. Treatment safety was evaluated through the assessment of haematological and biochemical parameters in blood, weight, and gastrointestinal alterations. Assessment was carried out before, between and after treatment series. Treatment with MTC-305 was effective at reducing parasite burdens and improving the animals' clinical picture. Dogs treated with this compound did not present significant toxicity signs. These results were superior to those obtained using the reference drug, meglumine antimoniate, in monotherapy. These results would support a broader clinical trial, optimised dosage, and an expanded follow-up stage to confirm the efficacy of this drug.

O-Alkyl Hydroxamates Display Potent and Selective Antileishmanial Activity.

Leishmania (L.) infantum causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that O-alkyl hydroxamate derivatives displayed potent and selective in vitro activity against the amastigote stage of L. infantum while no activity was observed against promastigotes. Compound 5 showed potent in vivo activity against L. infantum. Moreover, the combination of compound 5 supported on gold nanoparticles and meglumine antimoniate was also effective in vivo and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound 5 did not reach highly conserved pocket C and established interactions with the semiconserved residues V44, A45, R242, and E243 in pocket A of LiSIR2rp1. The surface space determined by these four amino acids is not conserved in human sirtuins. Compound 5 represents a new class of selective ligands with antileishmanial activity.

The electrokinetic characterization of gold nanoparticles, functionalized with cationic functional groups, and its' interaction with DNA.

Gold nanoparticles have attracted strong biomedical interest for drug delivery due to their low toxic nature, surface plasmon resonance and capability of increasing the stability of the payload. However, gene transfection represents another important biological application. Considering that cellular barriers keep enclosed their secret to deliver genes using nanoparticles, an important step can be achieved by studying the functionalization of nanoparticles with DNA. In the present contribution the synthesis of nanoparticles consisting of a gold core coated with one or more layers of amino acid (l-lysine), and cationic polyelectrolytes (poly-ethyleneimine and poly-l-lysine) is reported. All nanoparticles were subjected to dynamic light scattering, electrophoretic mobility measurements, UV-vis optical spectrophotometry analysis and transmission electron microscopy imaging. In addition, the adsorption of DNA plasmid (pSGS) with linear and supercoiled configurations was studied for those gold nanoparticles under the most suitable surface modifications. Preliminary results showed that the gold nanoparticles functionalized with poly-ethyleneimine and poly-l-lysine, respectively, and bound to linear DNA configurations, present in absolute value a higher electrophoretic mobility irrespective of the pH of the media, compared to the supercoiled and nicked configuration. The findings from this study suggest that poly-ethyleneimine and poly-l-lysine functionalized gold nanoparticles are biocompatible and may be promising in the chemical design and future optimization of nanostructures for biomedical applications such as gene and drug delivery.

Development of iron/ethylcellulose (core/shell) nanoparticles loaded with diclofenac sodium for arthritis treatment.

Diclofenac sodium is a non-steroidal anti-inflammatory drug of choice to treat arthritis because of its potential anti-inflammatory and analgesic activity. Because of its shorter biological half-life, it is needed to be given frequently and at high doses to elicit the required therapeutic activity, simultaneously leading to severe side effects. We hypothesized that the efficient delivery of diclofenac sodium to inflammation using a magnetic colloid could reduce the dose required to bring out sufficient therapeutic response. Hence, we have developed a diclofenac sodium-loaded magnetic nanomedicine, consisting of a magnetic core (iron) and a biocompatible polymeric shell (ethylcellulose) for parenteral administration. These core/shell nanoparticles were synthesized by an emulsion solvent evaporation process. Two drug loading methods were analyzed: the first one being drug addition prior to the emulsion solvent evaporation process (leading to drug entrapment into the polymeric network), and the second method based on diclofenac sodium surface adsorption onto the preformed nanoparticles. Compared to drug adsorption, the entrapment of this active agent into the polymeric matrix yielded a higher drug loading and a slower drug release profile. Such nanocomposites possessed very important characteristics such as unusually high drug loading, enhanced magnetic susceptibility and prolonged drug release, indicating their potential use as nanocarriers for efficient delivery of diclofenac sodium to inflammation sites.

Electrophoretic characterization of gold nanoparticles functionalized with human serum albumin (HSA) and creatine.

The synthesis of composite nanoparticles consisting of a gold core coated with a human serum albumin (HSA)/creatine layer is described, and their possible application as novel drug carriers for brain delivery is discussed. In this paper, the effect of the concentration of creatine and HSA in the different formulations is studied by electrophoretic mobility measurements as a function of pH and ionic strength. Due to the permeable character of the coatings surrounding the gold cores, an appropriate analysis of their electrophoretic mobility must be addressed. Recent developments of electrokinetic theories for particles covered by soft surface layers have rendered possible the evaluation of the softness degree from raw electrophoretic mobility data. In the present contribution, the data are quantitatively analyzed on the basis of three theoretical models of the electrokinetics of soft particles. As a result, information is obtained on both the surface potential and the charge density of the surrounding layer. The three models used reproduce properly the experimental behavior, although Duval and Ohshima's calculations appear to yield a more accurate fit of the data. It is shown that the albumin/nanogold particles absorb large amounts of creatine. In addition, the low surface charge and the albumin layer are expected to make it possible to deliver the particles through the blood-brain barrier.