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The liposomal amphotericin B (AmB) formulation, AmBisome®, still represents the best therapeutic option for cutaneous and visceral leishmaniasis. However, its clinical efficacy depends on the patient's immunological status, the clinical manifestation and the endemic region. Moreover, the need for parenteral administration, its side effects and high cost significantly limit its use in developing countries. This review reports the progress achieved thus far toward the understanding of the mechanism responsible for the reduced toxicity of liposomal AmB formulations and the factors that influence their efficacy against leishmaniasis. It also presents the recent advances in the development of more effective liposomal AmB formulations, including topical and oral liposome formulations. The critical role of the AmB aggregation state and release rate in the reduction of drug toxicity and in the drug efficacy by non-invasive routes is emphasized. This paper is expected to guide future research and development of innovative liposomal formulations of AmB. [ABSTRACT FROM AUTHOR]

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Cutaneous leishmaniasis (CL) is a neglected tropical skin disease caused by the protozoan genus Leishmania. The treatment is restricted to a handful number of drugs that exhibit toxic effects, limited efficacy, and drug resistance. Additionally, developing an effective topical treatment is still an enormous unmet medical challenge. Natural oils, e.g. the oleoresin from P. emarginatus fruits (SO), contain various bioactive molecules, especially terpenoid compounds such as diterpenes and sesquiterpenes. However, its use in topical formulations can be impaired due to the natural barrier of the skin for low water solubility compounds. Nanoemulsions (NE) are drug delivery systems able to increase penetration of lipophilic compounds throughout the skin, improving their topical effect. In this context, we propose the use of SO-containing NE (SO-NE) for CL treatment. The SO-NE was produced by a low energy method and presented suitable physicochemical characteristic: average diameter and polydispersity index lower than 180 nm and 0.2, respectively. Leishmania (Leishmania) amazonensis-infected BALB/c mice were given topical doses of SO or SO-NE. The topical use of a combination of SO-NE and intraperitoneal meglumine antimoniate reduced lesion size by 41 % and tissue regeneration was proven by histopathological analyses. In addition, a reduction in the parasitic load and decreased in the level of IFN-γ in the lesion may be associated, as well as a lower level of the cytokine IL-10 may be associated with a less intense inflammatory process. The present study suggests that SO-NE in combination meglumine antimoniate represents a promising alternative for the topical treatment of CL caused by L. (L.) amazonensis., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Repair of tissue damaged in diabetic wounds is essential to minimize the cases of amputation of the limbs in millions of diabetic people around the world. Although the all-trans retinoic acid (ATRA) is described as a potential wound healing agent, however its effects are controversial due to adverse reactions that may impair the wound healing during the treatment schedules. Our aim was to design and characterize an ATRA-loaded solid lipid nanoparticles surrounded by chitosan film to promote an ATRA controlled release and to evaluate its effectiveness in promoting wound healing in a diabetic mouse model. The SLN-ATRA were developed using biocompatible lipids without using organic solvent. The SLN-ATRA had high drug entrapment efficiency (98.0 %) and low polydispersity index (PDI) and average diameter, respectively, 0.24 ± 0.02 and 83.0 ± 6 nm. The transmission electron microscope (TEM) image presented that the SLN-ATRA were homogeneous in size and had spherical structures. The incorporation of SLN-ATRA in the chitosan films propitiated a homogeneous distribution of the drug and a controlled drug release. Furthermore, in vivo assay proved that chitosan films containing SLN-ATRA accelerated the closure of wounds of diabetic mice when compared to the control chitosan films without ATRA. SLN-ATRA chitosan films also reduced leukocyte infiltrate in the wound bed, improved collagen deposition, and reduced scar tissue. No sign of skin irritation was observed. These results indicated that SLN-ATRA surrounded in chitosan films are a promising candidate to treat diabetic wounds, improving tissue healing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Combination-based chemotherapies have been the standard treatment for multiple solid tumors since the 1960s. Combined therapies where both agents have toxicity results in dose-limiting effects. α- tocopherol succinate (TS) is an analogue of vitamin E that exhibits antitumor properties in the absence of toxicity. Hence, its combination with a frontline chemotherapy, doxorubicin (DOX) is an alternative to increase antitumor efficacy. Therefore, the aim of this work was to evaluate the antitumor activity of nanostructed lipid carriers (NLC) loaded with TS and DOX. The NLC-TS-DOX were prepared, characterized and radiolabeled with technetium-99m. Cytotoxicity studies were performed in vitro, using two breast cancer cell lines, MDA-MB-231 and 4T1. Biodistribution and antitumor activity were evaluated in 4T1 tumor-bearing mice. The results showed that NLC-TS-DOX had a small diameter (85 nm) and a long blood clearance (T 1/2 β = 1107.71 min) that consequently resulted in a higher tumor uptake compared to contralateral muscle for up to 48 h. Drug combination studies in MDA-MB-231 and 4T1 cells showed a combination index below 0.8 at ED 50-90 for both cell lines. Interestingly, a high synergism was found at ED 90. Antitumor activity showed a better control of tumor growth for animals treated with NLC-ST-DOX. The small particle size, along with the EPR effect and the controlled release of DOX from the particle, associated with the synergic combination between TS and DOX led to an increase of the antitumor efficacy. Therefore, NLC-TS-DOX can be considered a plausible alternative to improve antitumor efficacy in DOX therapeutic regimens., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Nowadays cancer is one of the most common causes of deaths worldwide. Conventional antitumor agents still present various problems related to specificity for tumor cells often leading to therapeutic failure. Nanoscale particles are considered potential alternative to direct access of drugs into tumor cells, therefore increasing the drug accumulation and performance. The aim of this study was to evaluate the antitumor activity of doxorubicin (DOX)-loaded nanostructured lipid carriers (NLC) versus liposomes against a breast cancer animal experimental model. NLC-DOX and liposomes-DOX were successfully prepared and characterized. Tumor-bearing mice were divided into five groups (blank-NLC, blank-liposome, DOX, NLC-DOX, liposome-DOX). Each animal received by the tail vein four doses of antitumoral drugs (total dose, 16mg/kg), every 3 days. Antitumor efficacy was assessed by measuring 1) tumor volume, calculating the inhibitory ratio (TV-IR, see after) and 2) acquiring scintigraphic images of the tumor using doxorubicin radiolabeled with technetium-99m as an imaging tumor probe. Liposome-DOX and free DOX did not showed differences in the tumor mean volume, whereas NLC-DOX proved to be the best treatments in controlling the tumor growth. NLC-DOX showed an inhibition ration (TV-IR) of 73.5% while free DOX and liposome-DOX decreased TV-RI of 48.8% and 68.0%, respectively. Tumor was clearly visualized in controls, DOX, and liposome-DOX groups. Yet, regarding the NLC-DOX group, tumor was barely identified by the image, indicating antitumor efficacy. Moreover, both NLC and liposomes proved to be able to delay the occurrence of lung metastasis. In conclusion, results of this study indicated that NLC-DOX might be an alternative strategy to achieve an efficient antitumor activity., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

This work aimed to develop solid lipid nanoparticles (SLN) co-loaded with doxorubicin and α-tocopherol succinate (TS) and to evaluate its potential to overcome drug resistance and to increase antitumoral effect in MCF-7/Adr and NCI/Adr cancer cell lines. The SLN were prepared by a hot homogenization method and characterized for size, zeta potential, entrapment efficiency (EE), and drug loading (DL). The cytotoxicity of SLN or penetration was evaluated in MCF-7/Adr and NCI/adr as a monolayer or spheroid cancer cell model. The SLN showed a size in the range of 74-80nm, negative zeta potential, EE of 99%, and DL of 67mg/g. The SLN co-loaded with Dox and TS showed a stronger cytotoxicity against MCF-7/Adr and NCI/Adr cells. In the monolayer model, the doxorubicin co-localization as a free and encapsulated form was higher for the encapsulated drug in MCF-7/Adr and NCI/adr, suggesting a bypassing of P-glycoprotein bomb efflux. For cancer cell spheroids, the SLN co-loaded with doxorubicin and TS showed a prominent cytotoxicity and a greater penetration of doxorubicin., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This work aimed to develop solid lipid nanoparticles (SLN) co-loaded with doxorubicin and α-tocopheryl succinate (TS), a succinic acid ester of α-tocopherol that exhibits anticancer actions, evaluating the influence of TS on drug encapsulation efficiency. The SLN were characterized for size, zeta potential, entrapment efficiency (EE), and drug release. Studies of in vitro anticancer activity were also conducted. The EE was significantly improved from 30 ± 1% to 96 ± 2% for SLN without and with TS at 0.4%, respectively. In contrast, a reduction in particle size from 298 ± 1 to 79 ± 1 nm was observed for SLN without and with TS respectively. The doxorubicin release data show that SLN provide a controlled drug release. The in vitro studies showed higher cytotoxicity for doxorubicin-TS-loaded SLN than for free doxorubicin in breast cancer cells. These findings suggest that TS-doxorubicin-loaded SLN is a promising alternative for the treatment of cancer., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A nanostructured lipid carrier (NLC) loaded with doxorubicin (DOX) has been shown to be cytotoxic against the human cancer cell lines A549 and MCF-7/Adr. In attempts to improve formulation characteristics, enhance pharmacokinetics and antitumor effects, we modified the surface of these NLC with an alternating layer-by-layer (LbL) assembly of polycation and polyanion polyelectrolytes and an additional coating with PEG using a simple method of core shell attachment. The formulation had a narrow size distribution, longer residence in the blood, lower accumulation in the liver, higher accumulation in tumors and a significant tumor growth inhibition effect. Thus, NLC-DOX nanopreparations complexes modified by LbL coating have the potential to enhance the anticancer effects of DOX against tumors., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Topical chemotherapy with paromomycin (PA) has been used as an alternative for the treatment of cutaneous leishmaniasis; however, poor skin penetration of this drug limits the efficacy of formulations. The objective of this work was to study the ability of the PA free base to form ion pairing with organic acids, as well as evaluate the effect of these compounds on the topical delivery of PA. PA permeation across intact skin was low, while drug penetration into skin from PA ion pairing was the higher than that observed for the PA base. Data obtained on the stripped skin, a damaged skin model, clearly showed that the ion pairing presented a potential to improve PA skin permeation.

Previous studies demonstrated that proteinases from latex of C. candamarcensis act as mitogens on fibroblast and epithelial cells and a subsequent report showed their protective, angiogenic and wound healing effects on gastric ulcers. In this study, we present evidence of skin healing activity by the group of proteinases known as P1G10. By using a hairless mouse model, we compared the healing effect following topical application of various concentrations of P1G10. The data confirm that healing actions take place between 0.1 and 1%, without adverse local irritation or systemic toxicological action after a prolonged period of use. The wound healing effect is unaltered when P1G10 is previously inhibited with iodoacetamide. The low permeation of the hydrosoluble formulation Polawax(®) supports the maintenance of the drug at the site of application. These results extend the healing properties of these groups of enzymes in situations of dermatological trauma and open the way to future clinical applications.

The present study aimed to evaluate the potential of liposomes loaded with paromomycin (PA), an aminoglycoside antibiotic associated with poor skin penetration, for the topical treatment of cutaneous leishmaniasis (CL). Fluid liposomes were prepared and characterized for particle size, zeta potential, and drug entrapment. Permeation studies were performed with two in vitro models: intact and stripped skin. The antileishmanial activity of free and liposomal PA was evaluated in BALB/c mice infected by Leishmania (L.) major. Drug entrapment ranged from 10 to 14%, and the type of vesicle had little influence on this parameter. Particle size and polydispersity index of the vesicles composed by phosphatidylcholine (PC) and PC/cholesterol (Chol) ranged from of 516 to 362 nm and 0.7 to 0.4, respectively. PA permeation across intact skin was low, regardless of the formulation tested, while drug penetration into skin (percent of the applied dose) from PC (7.2 +/- 0.2%) and PC/Chol (4.8 +/- 0.2%) liposomes was higher than solution (1.9 +/- 0.1%). PA-loaded liposomes enhanced in vitro drug permeation across stripped skin and improved the in vivo antileishmanial activity in experimentally infected mice. Our findings suggest that the liposomes represent a promising alternative for the topical treatment of CL using PA.

Whether ultradeformable vesicles pass intact through the stratum corneum and can promote the transdermal absorption of any substance remain open questions. This paper presents different experimental approaches, based on the use of calcein as hydrophilic fluorescent marker, to probe the physicochemical and pharmacokinetic characteristics of these vesicles. Ultradeformable membranes made from natural phosphatidylcholine and sodium cholate were found to be highly permeable to calcein, as a result of the permeabilizing effects of sodium cholate and ethanol. In vitro skin permeation and in vivo transdermal (percutaneous) absorption studies were performed using hairless mice. Both studies indicated that deformable vesicles reduce the transdermal flux of calcein, when compared to a solution containing or not sodium cholate and ethanol. The data support the model that the transdermal absorption of calcein from deformable vesicles is controlled by the release of the drug from the formulation deposited onto the skin surface. Importantly, fluorescence measurements of the receptor fluid of the Franz diffusion cell after addition of Co(2+) quencher revealed that permeated calcein exists essentially under the non-encapsulated form. In conclusion, our results argue against the model that deformable vesicles would carry hydrophilic drugs across the skin and act as a sustained release system in deep tissues., (Copyright 2009 Elsevier B.V. All rights reserved.)

This work aims to investigate the influence of the formation of ion pairing between all-trans retinoic acid (RA) and a lipophilic amine (stearylamine; STE) on the drug encapsulation efficiency (EE) and stability of solid lipid nanoparticles (SLNs). The SLNs were characterized for EE and size. The EE and particle size were significantly improved and reduced, respectively, when the surfactant or co-surfactant concentration increased. However, while the formulation without STE allowed only 13% of RA encapsulation, the EE for RA-STE-loaded SLNs was 94%. The stability studies showed a significant decrease in EE for the SLNs without STE, while, for SLNs loaded with RA and STE, the EE remained constant after 360 days. The interactions among ion pairing components and the lipid matrix were investigated through small-angle X-ray scattering (SAXS). The SAXS analysis revealed the presence of RA in the crystalline form in SLNs without ion pairing, while crystalline RA was not observed in SLNs loaded with RA/amine. Skin irritation studies showed that the SLNs loaded with the ion pairing were significantly less irritating when compared to the marketed RA-cream. This novel SLN formulation represents a promising alternative for topical treatment of acne with RA.

The bis-triazole antifungal fluconazole (FCZ) is used in the systemic treatment of superficial mycoses. The inconvenience of drug interactions and incidence of adverse reactions occurs in approximately 16% of patients, despite several advantages against systemic fungal infections. Because its pharmacokinetics profile is favorable to cutaneous accumulation, it presents a prominent importance in the treatment of superficial mycoses. This study shows FCZ method validation by reversed-phase high-performance liquid chromatography in the linear range of 2 to 32 microg/mL, which suitable for application in biological matrices after topical permeation studies. The method is tested in simulated FCZ alcoholic solution applied to skin extracts after in vitro permeation studies using Franz cells. Recovery shows good results (in the range 75.0% +/- 4.1% to 82.0% +/- 6.6%) regarding the biological matrices.

It has been previously reported that beta-cyclodextrin (beta-CD) enhances the oral absorption of the pentavalent antimony (Sb) drug, meglumine antimoniate (MA). Contrary to the drugs commonly used in association with beta-CD, MA is highly soluble in water (solubility >300 mg/mL) and, therefore, the mode of action of beta-CD in this system requires clarification. ESI(-)-MS analysis of MA and of the MA/beta-CD composition indicated the formation of a 1:1 association compound between 1:1 Sb-meglumine complex and beta-CD. A stability constant on the order of 100 Lmol(-1) was determined for this association compound. When MA solution was heated for 48 h at 55 degrees C to mimic the conditions used to prepare MA/beta-CD, MA was found to suffer dissociation, from high molecular weight Sb complexes into species of lower molecular weight. Strikingly, heated MA was found to be more extensively absorbed in mice by the oral route than MA freshly prepared at room temperature. In vitro skin permeation experiments using MA and MA/beta-CD indicated a two-fold increase in the Sb flux for MA/beta-CD. These findings support the hypothesis that the improved oral absorption of Sb arises from the increased permeation of MA across lipid bilayers, as a result of the enhanced availability of 1:1 Sb-meglumine complex.