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The short-lived peptide, angiotensin-(1-7) (Ang-(1-7)), was encapsulated in different liposome preparations, in order to evaluate the influence of membrane fluidity, membrane surface, liposome size and dose of peptide on the cardiovascular effects of the encapsulated peptide at a specific site of the brain. These preparations were microinjected unilaterally into the rostral ventrolateral medulla (RVLM) of Wistar rats, and mean arterial blood pressure (MAP) and heart rate (HR) were registered by telemetry. Pegylated, rigid and calibrated (200 nm) liposomes, containing 50 ng of Ang-(1-7), elicited a significant increase of MAP for at least 7 days, in contrast to empty liposomes or non-pegylated liposomes. When a two-fold higher peptide dose was employed or when pegylated liposomes were used in the fluid state or uncalibrated, less pronounced pressor effects were observed. These data show that the cardiovascular responses to the microinjection of Ang-(1-7)-containing liposomes into the RVLM can be modulated through the manipulation of liposome characteristics. These results can be explained by the influence of liposome characteristics on the flux of peptide release. It is expected that this new method will encounter numerous applications in the study of the chronic actions of short-lived bioactive peptides in specific sites of the brain. [Copyright &y& Elsevier]

The aim of the present study was to evaluate the ability of liposomes to improve the efficacy of tartar emetic (TA) against established Schistosoma mansoni infection. TA was used as a schistosomicidal drug model and both conventional liposomes (CL) and long-circulating pegylated liposomes (LCL) were evaluated. In the first experiment, TA, either free or encapsulated within CL or LCL, was given intraperitoneally (i.p.) as a single dose of 11 mg Sb/kg to mice experimentally infected with S. mansoni. Only the group treated with LCL showed a significant (55%) reduction in the worm burden, compared to the control groups (untreated or treated with empty LCL). In the second experiment, the efficacy of TA-containing LCL was evaluated at a higher dose (27 mg Sb/kg) by both subcutaneous (s.c.) and i.p. routes. Reduction levels of 67 and 82% were achieved by s.c. and i.p. routes, respectively. Strikingly, all mice survived to this high dose of antimony. This is in contrast with free TA that was lethal in 100% of mice at the same dose. The present work demonstrates that LCL reduce the acute toxicity of TA and effectively deliver this drug to S. mansoni during the late stages of parasite infection. [Copyright &y& Elsevier]

• First report of antileishmanial activity of fullerol. • Fullerol reduces hepatic parasite load in murine model of visceral leishmaniasis. • Liposome encapsulation of fullerol enhances its antileishmanial activity in vivo. • An innovative therapeutic approach based on the association of two nanosystems. Visceral leishmaniasis (VL) is a systemic parasitic disease that leads to high rates of morbidity and mortality in humans worldwide. There is a great need to develop new drugs and novel strategies to make chemotherapy for this disease more efficacious and well tolerated. Recent reports on the immunomodulatory effects and the low toxicity of the spherical carbon nanostructure fullerol led us to investigate in vitro and in vivo antileishmanial activity in free and encapsulated forms in liposomes. When assayed against intramacrophagic Leishmania amastigotes, fullerol showed a dose-dependent reduction of the infection index with IC 50 of 0.042 mg/mL. When given daily by i.p. route for 20 days (0.05 mg/kg/d) in a murine model of acute VL, fullerol promoted significant reduction in the liver parasite load. To improve the delivery of fullerol to the infection sites, liposomal formulations were prepared by the dehydration-rehydration method. When evaluated in the acute VL model, liposomal fullerol (Lip-Ful) formulations given i.p. at 0.05 and 0.2 mg/kg with 4-days intervals were more effective than the free form, with significant parasite reductions in both liver and spleen. Lip-Ful at 0.2 mg/kg promoted complete parasite elimination in the liver. The antileishmanial activity of Lip-Ful was further confirmed in a chronic model of VL. Lip-Ful was also found to induce secretion of pro-inflammatory TNF-α, IFN-γ and IL-1β cytokines. In conclusion, this work reports for the first time the antileishmanial activity of fullerol and introduces an innovative approach for treatment of VL based on the association of this nanostructure with liposomes. [ABSTRACT FROM AUTHOR]

Re-emergence and geographic expansion of leishmaniasis is accelerating efforts to develop a safe and effective Leshmania vaccine. Vaccines using Leishmania recombinant antigens, such as LiHyp1, which is mostly present in the amastigote parasite form , are being developed as a next generation to crude killed parasite-based vaccines. The main objective of this work was to develop a LiHyp1-based vaccine and determine if it can induce protective immunity in BALB/c mice when administered using a dissolvable microneedle (DMN) patch by the skin route. The LiHyp1 antigen was incorporated into cationic liposomes (CL), with or without the TLR9 agonist, CpG. The LiHyp1-liposomal vaccines were characterized with respect to size, protein encapsulation rates and retention of their physical characteristics after incorporation into the DMN patch. DMN mechanical strength and skin penetration ability were tested. A vaccine composed of LiHyp1, CpG and liposomes and subcutaneously injected or a vaccine containing antigen and CpG in DMN patches, without liposomes, induced high antibody responses and significant levels of protection against L. donovani parasite infection. This study progresses the development of an efficacious leishmania vaccine by detailing promising vaccine formulations and skin delivery technologies and it addresses protective efficacy of a liposome-based dissolvable microneedle patch vaccine system. [ABSTRACT FROM AUTHOR]

There is no safe and efficacious vaccine against human leishmaniasis available and live attenuated vaccines have been used as a prophylactic alternative against the disease. In order to obtain an attenuated Leishmania parasite for vaccine purposes, we generated L. infantum KHARON1 (KH1) null mutants (ΔLikh1). This gene was previously associated with growth defects in L. mexicana. ΔLikh1 was obtained and confirmed by PCR, qPCR and Southern blot. We also generate a KH1 complemented line with the introduction of episomal copies of KH1. Although ΔLikh1 promastigote forms exhibited a growth pattern similar to the wild-type line, they differ in morphology without affecting parasite viability. L. infantum KH1-deficient amastigotes were unable to sustain experimental infection in macrophages, forming multinucleate cells which was confirmed by in vivo attenuation phenotype. The cell cycle analysis of ΔLikh1 amastigotes showed arrested cells at G2/M phase. ΔLikh1-immunized mice presented reduced parasite burden upon challenging with virulent L. infantum, when compared to naïve mice. An effect associated with increased Li SLA-specific IgG serum levels and IL-17 production. Thus, ΔLikh1 parasites present an infective-attenuated phenotype due to a cytokinesis defect, whereas it induces immunity against visceral leishmaniasis in mouse model, being a candidate for antileishmanial vaccine purposes. [ABSTRACT FROM AUTHOR]