Potential of the association of dodecyl gallate with nanostructured lipid system as a treatment for paracoccidioidomycosis: In vitro and in vivo efficacy and toxicity

Abstract

Paracoccidioidomycosis (PCM) is a systemic mycosis endemic in Latin America, caused by Paracoccidioides spp. A limited number of antifungal agents are available and the search for new compounds has increased. Additionally, nanostructured lipid system (NLS) has emmerged as an interesting strategy to carrier compounds for the treatment of mycosis. In this work, the antifungal efficacy and toxicity of dodecyl gallate (DOD) associated with a NLS was evaluated through in vitro and in vivo tests. DOD showed good in vitro antifungal activity and low toxicity in lung fibroblasts and zebrafish embryos, but no antifungal efficacy in infected mice, which may have been a result of low bioavailability. On the other hand, the association of DOD + NLS was beneficial and resulted in lower toxicity in lung fibroblasts and zebrafish embryos. In addition, NLS + DOD promoted a significant reduction in the fungal burden of mice lungs and could be a potential therapeutic option against PCM.

Incorporation of Nonyl 3,4-Dihydroxybenzoate Into Nanostructured Lipid Systems: Effective Alternative for Maintaining Anti-Dermatophytic and Antibiofilm Activities and Reducing Toxicity at High Concentrations

“…Our results showed that the incorporation of nonyl into NLS reduced toxicity in the embryos by 12.7 times, showing an increase in the therapeutic margin through incorporation. Similar results were obtained by Singulani et al (2018), when the compound derived from gallic acid, dodecyl gallate was incorporated into an NLS using another surfactant, Brij R 35.…”

“…The NLS characterization tests showed that the incorporation of nonyl into the NLS caused a small variation in the size of the particles. The values obtained are in the range from 10 to 250 nm (100-2500 Å), which is considered an ideal range for nanostructured lipid systems of the microemulsion type, according to Formariz et al (2005) and Singulani et al (2018). When comparing the control formulation (NLS) and the formulation containing the incorporated compound (NLS + nonyl), there is a small increase in the size of the particles, which is a strong indication that the sample has been incorporated into the lipid system.…”

“…The susceptibility tests show a variation in MIC values between the free and nonyl incorporated to the NLS of only one dilution for T. rubrum and eight dilutions for T. mentagrophytes. Some authors claim that there is no significance in varying up to two dilutions in microdilution assays (Pfaller et al, 2011;Singulani et al, 2018). Regarding the nonyl compound 3,4dihydroxybenzoate, the influence of the hydrophobic carbon chain on antifungal activity has been demonstrated, in addition to the fact that its antimicrobial effect increases with the addition of the side alkyl chain (Soares et al, 2014).…”

Decyl Gallate as a Possible Inhibitor of N-Glycosylation Process in Paracoccidioides lutzii

“…For this, cells were separated in two groups: (i) cells with only one or without any buds and (ii) cells with more than one bud. In the CFU enumeration assay, an aliquot of 100 l was diluted (1:100) in PBS and plated on solid BHI medium supplemented with 4% fetal calf serum, 5% P. brasiliensis (strain 192)-spent culture medium, 1.5% glucose, and gentamicin (40 mg/ml) and incubated at 37°C for 15 days, and colonies were counted (46). For the MTT assay, the 96-well plate was centrifuged for 2 min at 5,000 rpm.…”

“…Subsequently, 15 g/ml of ketoconazole (Sigma) in DMEM was added for 1 h at 37°C to kill only the adhered fungi, followed by PBS washes to remove them. The A549 cells were lysed with 100 l of sterile MilliQ water (32), and the suspension was plated on solid BHI medium supplemented as described previously and incubated at 37°C for 15 days for colony counts (46). The CFU count obtained indicates fungal cells that were internalized.…”