Depot Subcutaneous Injection with Chalcone CH8-Loaded Poly(Lactic-Co-Glycolic Acid) Microspheres as a Single-Dose Treatment of Cutaneous Leishmaniasis

Abstract

Conventional chemotherapy of cutaneous leishmaniasis (CL) is based on multiple parenteral or intralesional injections with systemically toxic drugs. Aiming at a single-dose localized therapy, biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with 7.8% of an antileishmanial nitrochalcone named CH8 (CH8/PLGA) were constructed to promote sustained subcutaneous release. , murine macrophages avidly phagocytosed CH8/PLGA smaller than 6 μm without triggering oxidative mechanisms. Upon 48 h of incubation, both CH8 and CH8/PLGA were 40 times more toxic to intracellular than to macrophages. , BALB/c were given one or three subcutaneous injections in the infected ear with 1.2 mg/kg of CH8 in free or CH8/PLGA forms, whereas controls received three CH8-equivalent doses of naked PLGA microparticles or meglumine antimoniate (Glucantime; Sanofi-Aventis). Although a single injection with CH8/PLGA reduced the parasite loads by 91%, triple injections with free CH8 or CH8/PLGA caused 80 and 97% reductions, respectively, in relation to saline controls. Meglumine antimoniate treatment was the least effective (only 36% reduction) and the most toxic, as indicated by elevated alanine aminotransferase serum levels. Together, these findings show that CH8/PLGA microparticles can be effectively and safely used for single-dose treatment of CL.

Improved drug loading via spray drying of a chalcone implant for local treatment of cutaneous leishmaniasis

“…Antileishmanial activity All CH8 formulations were active against intracellular amastigotes of L. amazonensis. As demonstrated before, encapsulation of CH8 in PLGA microparticles preserved the CH8 antileishmanial activity [19] and the addition of PVP in the polymeric matrix did not modify this effect. Nonetheless, encapsulation of CH8 into microparticles slightly increased its IC 50 from 0.4 mg/ml (free CH8) to 0.9-1.9 mg/ml (CH8 loaded polymeric microparticles), as shown in Figure 4.…”

“…CH8-loaded polymeric microparticles were also produced by emulsification-solvent evaporation method. The preparation protocol was previously described by our group [19]. In our previous studies, a maximum CH8 loading of 7.8% was obtained by following this experimental protocol.…”

“…Recently our group produced a PLGA microparticle implant loaded with 7.8% of CH8 prepared by emulsion-solvent evaporation method. This formulation administrated in a single dose by intralesional route demonstrated the same efficacy than the free drug in three doses in mice infected with L. amazonensis [19]. However, the emulsion-solvent evaporation method has many process variables that can hinder the scale up.…”

Nanomedicines for Cutaneous Leishmaniasis

“…Interest in designing nanomedicines for CL has grown over the years, as seen by the steady increase in scientific publications. Several nanosystems, such as liposomes [10][11][12][13][14][15][16][17][18][19][20], solid lipid nanoparticles [21,22], lipid complexes [23,24], lipid-core nanocapsules [25], polymeric particles [26][27][28][29][30][31], inorganic nanoparticle [32][33][34][35], cyclodextrins complexes [36,37], and drug nanoparticles [38] have been tested in vivo by different routes in experimental mouse and hamster models to improve CL treatment as summarized in Table 1 amphotericin B has been approved for human leishmaniasis so far, but that is restricted to VL and the more severe mucosal form of CL. Additional studies and clinical trials are needed to validate the potential of those experimental nanomedicines in human CL.…”

“…Recently, the safety and efficacy of PLGA microparticles containing chalcone CH8 in the intralesional treatment was demonstrated in L. amazonensis-infected BALB/c mice. Even a single subcutaneous injection with CH8-loaded particles was effective in controlling parasite growth, superior than three injections with the free drug or Glucantime ® , demonstrating the promising use of these systems in local and single-dose treatment of CL [31].…”