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

Yeimy J Rodriguez,Jean C Villamil,Luis F Quejada,Claudia M Parra-Giraldo,Yolima Baena,Leon D Perez

doi:10.3390/pharmaceutics12030196

Yeimy J Rodriguez, Jean C Villamil + Show 4 more

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https://doi.org/10.3390/pharmaceutics12030196

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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.

Highlights

During the last decades, the number of people susceptible to the invasive fungal disease (IFD) has increased
The diagnosis and treatment of IFD is difficult in many cases due to the minimal specificity of its symptomatology, especially since the identification of the pathogen source has further become complex, mainly in hospital centres where technological resources are unavailable or do not employ a personnel trained for this purpose; resorting to empirical therapies, which implies the use of broad spectrum antifungal drugs [4]
Materials ε-Caprolactone (CL) 98%, methoxy-polyethylene glycol of 5 kDa and polyethylene glycol diol (PEG-diol) of 6 kDa, RET (95%), pyrene (99%), Amphotericin B (AmB) (98%), 4-(dimethylamino)pyridine (DMAP) (99%), Tin(II) 2-ethylhexanoate (Sn(Oct)2) (95%), succinic anhydride (≥99%), N,N -dicyclohexylcarbodiimide (DCC), triethylamine (TEA), resazurin sodium salt, ethylenediaminetetraacetic acid (EDTA), Methylthiazolyldiphenyl-tetrazolium bromide (MTT), Dulbecco’s Modified Eagle’s Medium (DMEN) and other reagents and solvents used in the protocols of synthesis, purification and characterization were purchased from Sigma-Aldrich, St

Summary

Introduction

The number of people susceptible to the invasive fungal disease (IFD) has increased. It is a consequence of advances in medicine that have increased the life expectancy of HIV-infected patients and augmented the number of procedures, such as organ and bone marrow transplants. Since 1959, Amphotericin B (AmB) has been the “gold standard” for the treatment of IFDs. Fungizone® (a colloidal dispersion of this drug is stabilized by sodium deoxycholate as a surfactant) is the most widely used formulation of AmB due to its effectiveness, wide spectrum of action and low number of reports of resistant strains [5,6,7]. High cost apart from high dose (5–10 mg/kg for Ambisome® compared with 0.5–1 mg/kg for Fungizone®) requirements are disadvantageous, principally among low- and middle-income countries, such as Colombia [13,14,15,16,17]

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