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Anionic Polymerization of an Amphiphilic Copolymer for Preparation of Block Copolymer Micelles Stabilized by π-π Stacking Interactions
Published on: October 10, 2016
Development of Amphotericin B Micellar Formulations Based on Copolymers of Poly(ethylene glycol) and
Yeimy J Rodriguez1, Luis F Quejada2, Jean C Villamil2
1Grupo de Investigación en Macromoléculas, Facultad de Ciencias, Departamento de Química, Universidad Nacional de Colombia-Sede Bogotá, Carrera 45 N° 26-85, edificio 451 of. 449 Bogotá, Colombia.
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.
Insights
This study developed novel retinol-conjugated polymer micelles for Amphotericin B (AmB) delivery. These micelles reduce AmB toxicity and enhance its antifungal efficacy against Candida strains.
Area of Science:
- Polymer Chemistry
- Nanotechnology
- Pharmacology
Background:
- Amphotericin B (AmB) is a broad-spectrum antifungal drug with significant toxicity, including renal failure.
- Existing nanoencapsulation methods for AmB often suffer from low encapsulation efficiency.
- Developing safer and more effective AmB delivery systems is crucial for treating invasive fungal infections.
Purpose of the Study:
- To create micellar delivery systems for AmB using retinol (RET)-conjugated amphiphilic block copolymers (ABCs).
- To reduce AmB toxicity while maintaining or improving its antifungal activity.
- To enhance the encapsulation efficiency of AmB in polymeric micelles.
Main Methods:
- Synthesis of poly(ε-caprolactone)-polyethylenglycol (PCL-PEG) block copolymers (AB and ABA types) via ring-opening polymerization.
- Conjugation of copolymers with retinol (RET) using Steglich esterification.
- Characterization of copolymers and conjugates using 1H-NMR spectroscopy and gel permeation chromatography.
- Preparation and evaluation of AmB-loaded polymer micelles, assessing haemolytic effect and antifungal activity against Candida species.
Main Results:
- Retinol conjugation significantly enhanced AmB encapsulation capacity from ~2 wt% to 10 wt%.
- AmB-loaded micelles exhibited reduced haemolytic effects compared to free AmB.
- Encapsulated AmB demonstrated improved antifungal efficacy against Candida albicans and Candida auris, indicated by lower minimum inhibitory concentrations (MICs).
Conclusions:
- Retinol-conjugated amphiphilic block copolymers provide an effective platform for developing low-toxicity, high-efficiency Amphotericin B delivery systems.
- The developed micellar system offers a promising strategy to improve the therapeutic index of Amphotericin B.
- This approach holds potential for safer and more effective treatment of invasive fungal infections.
