Combination oral therapy against Leishmania amazonensis infection in BALB/c mice using nanoassemblies made from amphiphilic antimony(V) complex incorporating miltefosine

8p.-3 fig.-1 tab.Clinically available drugs for mucocutaneous and cutaneous leishmaniases (CL) include mainly pentavalent antimony (Sb(V)) complexes, liposomal amphotericin B, and miltefosine (HePC). However, they present at least one of the following limitations: long-term parenteral administration through repeated doses, severe side effects, drug resistance, and high cost. HePC is the only oral drug available, but the appearance of resistance has resulted in changes of its use from monotherapy to combination therapy. Amphiphilic Sb(V) complexes, such as SbL8 obtained from reaction of Sb(V) with N-octanoyl-N-methylglucamide, were recently found to be orally active against experimental CL. The property of SbL8 to self-assemble in aqueous solution, forming nanostructures, led us to investigate the incorporation of HePC into SbL8 nanoassemblies and the therapeutic efficacy of SbL8/HePC nanoformulation by oral route in a murine model of CL. HePC incorporation into the SbL8 nanosystem was evidenced by using a fluorescent analog of HePC. The antileishmanial activity of SbL8/HePC nanoassemblies was evaluated after daily oral administration for 30 days in Leishmania amazonensis-infected BALB/c mice, in comparison with monotherapies (SbL8 or HePC) and saline control. All the treatments resulted in significant reduction in the lesion size growth, when compared with control. Strikingly, only SbL8/HePC nanoassemblies promoted a significant decrease of the parasite burden in the lesion. This work establishes the therapeutic benefit of SbL8/HePC association by oral route in a CL model and constitutes an important step towards the development of new orally active drug combination.This work was supported by the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant number: 425332/2018–7), Coordenação de Aperfeicoamento de Pessoal de Nível Superior (CAPES, grant number: PNPD20131163), and Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG, grant number: APQ-03129-16) for financial support. F.F. was recipient of fellowship from CNPq (grant number: 305659/2017-0) and Chaire Jean d’Alembert, Université Paris-Saclay, France (ANR-11-IDEX-0003-02). L.R was supported by Program of Redes Temáticas de Investigación Cooperativa RETICS-FEDER (grant number: RD16/0027/0010).Peer reviewe

Seasonality study of essential oil from leaves of Cymbopogon densiflorus and nanoemulsion development with antioxidant activity.

The development of formulations that maintain the biological and physical chemistry properties of essential oils is an important choice when they are used as an active ingredient. This study aimed to characterize the essential oil from leaves of Cymbopogon densiflorus and evaluate the antioxidant activity of the oil, and to produce a nanoemulsion formulation containing it. The essential oil was obtained by hydrodistillation, and seasonality was analysed every 2 months by gas chromatography?mass spectrometry, showing that more than 90% of the composition was maintained for the whole period and that the major compounds were trans?p?menta?2,8?dien?1?ol, cis?p?menta?2,8?dien?1?ol, trans?p?menta?1(7),8?dien?2?ol, cis?piperitol, and cis?p?menta?1(7),8?dien?2?ol. Stable nanoemulsions were prepared by phase inversion method encapsulating the essential oil. The antioxidant activity was evaluated by 2,2?diphenyl?1?picrylhydrazyl (DPPH) free radical scavenging and 2,2??azino?bis(3?ethylbenzothiazoline?6?sulphonic acid (ABTS) methods. In the first test, free and nanoemulsified essential oil showed half?maximal inhibitory concentration (IC50) values equivalent to 14.689 and 3.692 mg mL?1, respectively. In the second test, these values were 0.567 and 0.43 mg mL?1. The development of nanoemulsion?based essential oil from leaves of C. densiflorus was viable, and the formulated oil was able to reproduce the antioxidant activity at a concentration four times lower than that of the pure essential oil

The coenzyme A precursor pantethine enhances antitumor immunity in sarcoma

International audienceWe have previously identified the Vanin1 pathway as a tumor suppressor of sarcoma development via vitamin B5 and coenzyme A regeneration. Using an aggressive sarcoma cell line that lacks Vnn1 expression, we showed that the administration of pantethine, a vitamin B5 precursor, attenuates tumor growth in immunocompetent but not nude mice. Pantethine boosts antitumor immunity, including the polarization of myeloid and dendritic cells towards enhanced IFNγ-driven antigen presentation pathways and improved the development of hypermetabolic effector CD8 + T cells endowed with potential antitumor activity. At later stages of treatment, the effect of pantethine was limited by the development of immune cell exhaustion. Nevertheless, its activity was comparable with that of anti-PD1 treatment in sensitive tumors. In humans, VNN1 expression correlates with improved survival and immune cell infiltration in soft-tissue sarcomas, but not in osteosarcomas. Pantethine could be a potential therapeutic immunoadjuvant for the development of antitumor immunity

Nanostructured systems improve the antimicrobial potential of the essential oil from cymbopogon densiflorus leaves.

The physicochemical characteristics of nanostructured suspensions are important prerequisites for the success of new drug development. This work aimed to develop nanometric systems containing Cymbopogon densiflorus leaf essential oil and to evaluate their antimicrobial activity. The essential oil was isolated by hydrodistillation from leaves and analyzed by GC-MS. The main constituents were found to be trans-p-mentha-2,8-dien-1-ol, cis-p-mentha2,8-dien-1-ol, trans-p-mentha-1(7),8-dien-2-ol, cis-piperitol, and cis-p-mentha-1(7),8-dien-2-ol. In silico prediction analysis suggested that this oil possesses antimicrobial potential and the main mechanism of action might be the peptidoglycan glycosyltransferase inhibition. Nanoemulsions were prepared by the phase inversion method, and liposomes were made by the film hydration method. Qualitative evaluation of the antimicrobial activity was performed by the diffusion disk assay with 24 microorganisms; all of them were found to be sensitive to the essential oil. Subsequently, this property was quantified by the serial microdilution technique, where the nanoformulations demonstrated improved activity in comparison with the free oil. Bactericidal action was tested by the propidium iodide method, which revealed that free essential oil and nanoemulsion increased cytoplasmic membrane permeability, while no difference was observed between negative control and liposome. These results were confirmed by images obtained using transmission electron microscopy. This study has shown an optimization in the antimicrobial activity of C. densiflorus essential oil by a nanoemulsion and a liposomal formulation of the active substances