Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and Poly(ε-caprolactone) Conjugated with Retinol

Abstract

Amphotericin B (AmB) is a broad spectrum of antifungal drug used to treat antifungal diseases. However, due to the high toxicity of AmB, treated patients may suffer the risk of side effects, such as renal failure. Nanoencapsulation strategies have been reported to elicit low toxicity, albeit most of them possess low encapsulation efficiency. The aim of this research is to develop micellar delivery systems for AmB with reduced toxicity while maintaining its affectivity by employing retinol (RET)-conjugated amphiphilic block copolymers (ABCs) as precursors. Copolymers composed of poly(ε-caprolactone) (A) and polyethylenglycol (B) of types AB and ABA were synthesized by ring opening polymerization and subsequently conjugated with RET by Steglich esterification. 1H-NMR spectroscopy was used to corroborate the structure of copolymers and their conjugates and determine their molecular weights. Analysis by gel permeation chromatography also found that the materials have narrow distributions. The resulting copolymers were used as precursors for delivery systems of AmB, thus reducing its aggregation and consequently causing a low haemolytic effect. Upon conjugation with RET, the encapsulation capacity was enhanced from approximately 2 wt % for AB and ABA copolymers to 10 wt %. AmB encapsulated in polymer micelles presented improved antifungal efficiency against Candida albicans and Candida auris strains compared with Fungizone®, as deduced from the low minimum inhibitory concentration.

Antifungal Resistance in Candida auris: Molecular Determinants

“…The high rate of antifungal resistance of C. auris, and its great ability to form biofilms, creates the need to look for alternative treatments for the infections caused by this yeast. Among the alternatives that have been explored are natural peptides, phenolic compounds, nitric oxide in nanoparticles, as well as the reuse of drugs such as miltefosine and iodoquinol [11][12][13][14][15][16][17]99]. One of the natural peptides with antimicrobial activity is crotamine, a toxin obtained from the rattlesnake's venom [11].…”

“…Amphotericin B encapsulated in polymeric micelles has shown an improvement in antifungal efficiency, with MIC values of 0.93-1.865 mg/L against C. albicans and C. auris, compared to the MIC values (3.75 mg/L) of Fungizone ® . Thus, it is possible that infections caused by amphotericin-B-resistant C. auris are treated with the same antifungal but encapsulated in polymeric micelles [16].…”

“…The increase in the prevalence of multidrug-resistant C. auris to different groups of antifungals is a cause for alarm, especially considering that there are few treatment options nowadays. The latter has prompted the search for other therapeutic alternatives such as natural peptides, phenolic compounds, nitric oxide nanoparticles, as well as miltefosine and iodoquinol [11][12][13][14][15][16][17]. The conducted researches are promising, as they show that several of these alternatives can be used alone or in combination with other traditional antifungals, which produces a synergistic effect that potentiates fungal destruction.…”

Antifungal and Antiparasitic Drug Delivery

“…The originality of the new formulations proposed are usually based on the selection of already approved excipients along with the active components, such as Montanide™ Petgel A as vaccine adjuvant [1], poly(vinyl alcohol) [2], Poloxamer 407™ [3], a combination of Capryol 90™, Peceol™ and Labrasol™ [4], dextran and maltodextrin [5], a combination of modified chitosan nanoparticles with a standardized extract of cultured Lentinula edodes mycelia (AHCC™) [6], ground calcium carbonate [7], poly (d,l-lactide-co-glycolide) 50:50 [8] and Sepigel 305™ [9]. Only in one paper [10], authors have synthesized a new material based on copolymers of poly(ethyleneglycol) and poly(ε-caprolactone) conjugated with retinol as drug vehicle. Moreover, the characterization of the new formulations is described in detail in the ten papers with a special focus on toxicity and efficacy studies required in order to bring to the market these formulations.…”

“…This new formulation could be a promising alternative for topical treatment of cutaneous leishmaniasis. Rodriguez et al described the development of amphotericin B micellar formulations based on copolymers of poly(ethyleneglycol) and poly(ε-caprolactone) conjugated with retinol [10]. Biodegradable and biocompatible polymers were initially synthesized and then conjugated with retinol.…”